app.py

import glob
import smtplib
from datetime import datetime, timedelta
import itertools
import textwrap
from email.mime.multipart import MIMEMultipart
from email.mime.text import MIMEText
from email.utils import formatdate, make_msgid
from functools import cache
from math import pi
from time import sleep, time
from uuid import uuid4

import io
import os
from pathlib import Path
import sys

import pytz
from Bio import SeqIO
from Bio.Align import PairwiseAligner
from email_validator import validate_email, EmailNotValidError
import gradio as gr
import hydra
import pandas as pd
from pandarallel import pandarallel
import requests
from rdkit.DataStructs import BulkTanimotoSimilarity
from requests.adapters import HTTPAdapter, Retry
from markdown import markdown
from rdkit import Chem
from rdkit.Chem import AllChem, Draw, RDConfig, PandasTools, Descriptors, rdMolDescriptors, rdmolops, Lipinski, Crippen
from rdkit.Chem.Features.ShowFeats import _featColors
from rdkit.Chem.Scaffolds import MurckoScaffold
import py3Dmol

from bokeh.models import Legend, NumberFormatter, BooleanFormatter, HTMLTemplateFormatter, LegendItem
from bokeh.palettes import Category20c_20
from bokeh.plotting import figure
from bokeh.transform import cumsum
from bokeh.resources import INLINE
import seaborn as sns
import panel as pn

from apscheduler.schedulers.background import BackgroundScheduler
from tinydb import TinyDB, Query

#import swifter
from tqdm.auto import tqdm

from deepscreen.data.dti import validate_seq_str, rdkit_canonicalize, FASTA_PAT, SMILES_PAT
from deepscreen.predict import predict

sys.path.append(os.path.join(RDConfig.RDContribDir, 'SA_Score'))
import sascorer

DATASET_MAX_LEN = 10_240
SERVER_DATA_DIR = os.getenv('DATA')  # '/data'
DB_EXPIRY = timedelta(hours=48).total_seconds()

CSS = """
.help-tip {
  position: absolute;
  display: inline-block;
  top: 16px;
  right: 0px;
  text-align: center;
  border-radius: 40%;
  /* border: 2px solid darkred; background-color: #8B0000;*/
  width: 24px;
  height: 24px;
  font-size: 16px;
  line-height: 26px;
  cursor: default;
  transition: all 0.5s cubic-bezier(0.55, 0, 0.1, 1);
  z-index: 100 !important;
}

.help-tip:hover {
  cursor: pointer;
  /*background-color: #ccc;*/
}

.help-tip:before {
  content: '?';
  font-weight: 700;
  color: #8B0000;
  z-index: 100 !important;
}

.help-tip p {
  visibility: hidden;
  opacity: 0;
  text-align: left;
  background-color: #EFDDE3;
  padding: 20px;
  width: 300px;
  position: absolute;
  border-radius: 4px;
  right: -4px;
  color: #494F5A;
  font-size: 13px;
  line-height: normal;
  transform: scale(0.7);
  transform-origin: 100% 0%;
  transition: all 0.5s cubic-bezier(0.55, 0, 0.1, 1);
  z-index: 100;
}

.help-tip:hover p {
  cursor: default;
  visibility: visible;
  opacity: 1;
  transform: scale(1.0);
}

.help-tip p:before {
  position: absolute;
  content: '';
  width: 0;
  height: 0;
  border: 6px solid transparent;
  border-bottom-color: #EFDDE3;
  right: 10px;
  top: -12px;
}

.help-tip p:after {
  width: 100%;
  height: 40px;
  content: '';
  position: absolute;
  top: -5px;
  left: 0;
  z-index: 101;
}

.upload_button {
  background-color: #008000;
}

.absolute {
  position: absolute;
}

.example {
padding: 0;
background: none;
border: none;
text-decoration: underline;
box-shadow: none;
text-align: left !important;
display: inline-block !important;
}

footer {
visibility: hidden
}
"""


class View3DmolCell(py3Dmol.view):
    def __init__(self, width=320, height=200):
        divid = "3dmolviewer_UNIQUEID"
        self.uniqueid = None
        if isinstance(width, int):
            width = '%dpx' % width
        if isinstance(height, int):
            height = '%dpx' % height
        self.startjs = '''<div id="%s" style="position: relative; width: %s; height: %s;">
            </div>\n''' % (divid, width, height)
        self.startjs += '<script>\n'
        self.endjs = '</script>'

        self.updatejs = ''
        self.viewergrid = None

        self.startjs += 'viewer_UNIQUEID = $3Dmol.createViewer(document.getElementById("%s"),{backgroundColor:"white"});\n' % divid
        self.startjs += "viewer_UNIQUEID.zoomTo();\n"
        self.endjs = "viewer_UNIQUEID.render();\n" + self.endjs


FEAT_FACTORY = AllChem.BuildFeatureFactory(os.path.join(RDConfig.RDDataDir, 'BaseFeatures.fdef'))


def rgb_to_hex(rgb):
    rgb = tuple(round(i * 255) for i in rgb)
    return '#{:02x}{:02x}{:02x}'.format(rgb[0], rgb[1], rgb[2])


def mol_to_pharm3d(mol, mode='html'):
    try:
        # AllChem.Compute2DCoords(mol)
        mol = Chem.AddHs(mol)
        params = AllChem.ETKDGv3()
        params.randomSeed = 0xf00d  # for reproducibility
        AllChem.EmbedMolecule(mol, params)

        feats = FEAT_FACTORY.GetFeaturesForMol(mol)

        view = View3DmolCell(width=320, height=200)
        for feat in feats:
            pos = feat.GetPos()
            color = _featColors.get(feat.GetFamily(), (.5, .5, .5))
            view.addSphere({
                'center': {'x': pos.x, 'y': pos.y, 'z': pos.z},
                'radius': 0.5,
                'color': rgb_to_hex(color)
            })

        mol_block = Chem.MolToMolBlock(mol)
        view.addModel(mol_block, 'sdf')
        view.setStyle({'stick': {}})
        view.zoomTo()

        if mode == 'html':
            return view.write_html()
            # case 'png':
            #     return view.png()
    except Exception:
        return None


class HelpTip:
    def __new__(cls, text):
        return gr.HTML(
            # elem_classes="absolute",
            value=f'<div class="help-tip"><p>{text}</p>',
        )


TASK_MAP = {
    'Compound-Protein Interaction': 'DTI',
    'Compound-Protein Binding Affinity': 'DTA',
}

TASK_METRIC_MAP = {
    'DTI': 'AUROC',
    'DTA': 'CI',
    'Compound-Protein Interaction': 'AUROC',
    'Compound-Protein Binding Affinity': 'CI',
    'CPI': 'DTI',
    'CPA': 'DTA',
}

PRESET_MAP = {
    'DeepDTA': 'deep_dta',
    'DeepConvDTI': 'deep_conv_dti',
    'GraphDTA': 'graph_dta',
    'MGraphDTA': 'm_graph_dta',
    'HyperAttentionDTI': 'hyper_attention_dti',
    'MolTrans': 'mol_trans',
    'TransformerCPI': 'transformer_cpi',
    'TransformerCPI2': 'transformer_cpi_2',
    'DrugBAN': 'drug_ban',
    'DrugVQA-Seq': 'drug_vqa'
}

TARGET_FAMILY_MAP = {
    'General': 'general',
    'Kinase': 'kinase',
    'Non-Kinase Enzyme': 'non_kinase_enzyme',
    'Membrane Receptor': 'membrane_receptor',
    'Nuclear Receptor': 'nuclear_receptor',
    'Ion Channel': 'ion_channel',
    'Others': 'others',
    # 'general': 'general',
    # 'kinase': 'kinase',
    # 'non-kinase enzyme': 'non_kinase_enzyme',
    # 'membrane receptor': 'membrane_receptor',
    # 'nuclear Receptor': 'nuclear_receptor',
    # 'ion channel': 'ion_channel',
    # 'others': 'others',
}

TARGET_LIBRARY_MAP = {
    'DrugBank (Human)': 'drugbank_targets.csv',
    'ChEMBL33 (Human)': 'ChEMBL33_human_proteins.csv',
}

DRUG_LIBRARY_MAP = {
    'DrugBank (Human)': 'drugbank_compounds.csv',
    'Drug Repurposing Hub': 'drug_repurposing_hub.csv',
    'Enamine Discovery Diversity Set (DDS-10)': 'Enamine_Discovery_Diversity_Set_10_10240cmpds_20240130.csv',
    'Enamine Phenotypic Screening Library (PSL-5760)': 'Enamine_Phenotypic_Screening_Library_plated_5760cmds_2020_07_20.csv'
}

COLUMN_ALIASES = {
    'X1': 'Compound SMILES',
    'X2': 'Target FASTA',
    'ID1': 'Compound ID',
    'ID2': 'Target ID',
    'Y': 'Actual CPI/CPA',
    'Y^': 'Predicted CPI/CPA',
}

DRUG_SCRENN_CPI_OPTS = [
    'Calculate Max. Sequence Identity between the Input Target and Targets in the Training Set',
    'Calculate Max. Tanimoto Similarity between the Hit Compound and Known Ligands of the Input Target',
    'Calculate Max. Sequence Identity between the Input Target and Known Targets of Hit Compound',
]

DRUG_SCRENN_CPA_OPTS = [
    'Calculate Max. Sequence Identity between the Input Target and Targets in the Training Set',
]

TARGET_IDENTIFY_CPI_OPTS = [
    'Calculate Max. Tanimoto Similarity between the Input Compound and Compounds in the Training Set',
    'Calculate Max. Sequence Identity between the Identified Target and Known Targets of the Input Compound',
    'Calculate Max. Tanimoto Similarity between the Input Compound and Known Ligands of the Identified Target',
]

TARGET_IDENTIFY_CPA_OPTS = [
    'Calculate Max. Tanimoto Similarity between the Input Compound and Compounds in the Training Set',
]

pd.set_option('display.float_format', '{:.3f}'.format)
PandasTools.molRepresentation = 'svg'
PandasTools.drawOptions = Draw.rdMolDraw2D.MolDrawOptions()
PandasTools.drawOptions.clearBackground = False
PandasTools.drawOptions.bondLineWidth = 1
PandasTools.drawOptions.explicitMethyl = True
PandasTools.drawOptions.singleColourWedgeBonds = True
PandasTools.drawOptions.useCDKAtomPalette()
PandasTools.molSize = (100, 64)


def remove_job_record(job_id):
    # Delete the job from the database
    db.remove(Job.id == job_id)
    # Delete the corresponding files
    files = glob.glob(f"{SERVER_DATA_DIR}/{job_id}*")
    for file_path in files:
        if os.path.exists(file_path):
            os.remove(file_path)


def check_expiry():
    Job = Query()
    jobs = db.all()

    for job in jobs:
        # Check if the job has expired
        if job['status'] != 'RUNNING':
            expiry_time = job['expiry_time'] if job['expiry_time'] is not None else job['start_time'] + DB_EXPIRY
            if expiry_time < time():
                # Delete the job from the database
                db.remove(Job.id == job['id'])
                # Delete the corresponding file
                files = glob.glob(f"{SERVER_DATA_DIR}/{job['id']}*")
                for file_path in files:
                    if os.path.exists(file_path):
                        os.remove(file_path)
        elif job['status'] == 'RUNNING' and time() - job['start_time'] > 4 * 60 * 60:  # 4 hours
            # Mark the job as failed
            db.update({'status': 'FAILED',
                       'error': 'Job has timed out by exceeding the maximum running time of 4 hours.'},
                      Job.id == job['id'])
            if job.get('email'):
                send_email(job)


def smiles_to_ecfp(smiles):
    mol = Chem.MolFromSmiles(smiles)
    if mol:
        ecfp = AllChem.GetMorganFingerprintAsBitVect(mol, radius=2, nBits=2048)
    else:
        ecfp = []
    return ecfp


def max_tanimoto_similarity(smi, seen_smiles_with_fp):
    if smi is None or seen_smiles_with_fp is None or seen_smiles_with_fp.empty:
        return {'Max. Tanimoto Similarity': 0, 'Max. Tanimoto Similarity Compound': None}

    if smi in seen_smiles_with_fp['X1'].values:
        compound = smi
        if 'ID1' in seen_smiles_with_fp.columns:
            id1 = seen_smiles_with_fp.loc[seen_smiles_with_fp['X1'] == smi, 'ID1'].values[0]
            if pd.notnull(id1) and id1 != '':
                compound = id1
        return {'Max. Tanimoto Similarity': 1, 'Max. Tanimoto Similarity Compound': compound}

    mol = Chem.MolFromSmiles(smi)
    if mol is None:
        return {'Max. Tanimoto Similarity': 0, 'Max. Tanimoto Similarity Compound': None}

    mol_ecfp = AllChem.GetMorganFingerprintAsBitVect(mol, radius=2, nBits=2048)
    sims = pd.Series(BulkTanimotoSimilarity(mol_ecfp, seen_smiles_with_fp['FP'].values)).to_numpy()
    idx = sims.argmax()
    compound = seen_smiles_with_fp.iloc[idx]['X1']
    if 'ID1' in seen_smiles_with_fp.columns:
        id1 = seen_smiles_with_fp.iloc[idx]['ID1']
        if pd.notnull(id1) and id1 != '':
            compound = id1

    return {'Max. Tanimoto Similarity': sims[idx], 'Max. Tanimoto Similarity Compound': compound}


def alignment_score(query, target):
    aligner = PairwiseAligner()
    aligner.mode = 'local'
    alignment = aligner.align(query, target)
    return alignment.score / max(len(query), len(target))


def max_sequence_identity(seq, seen_fastas):
    if seq is None or seen_fastas is None or seen_fastas.empty:
        return {'Max. Sequence Identity': 0, 'Max. Sequence Identity Target': None}

    if seq in seen_fastas['X2'].values:
        target = seq
        if 'ID2' in seen_fastas.columns:
            id2 = seen_fastas.loc[seen_fastas['X2'] == seq, 'ID2'].values[0]
            if pd.notnull(id2) and id2 != '':
                target = id2
        return {'Max. Sequence Identity': 1, 'Max. Sequence Identity Target': target}

    cached_alignment_score = cache(alignment_score)
    max_iden = 0
    target = None
    for fasta in seen_fastas['X2'].values:
        identity = cached_alignment_score(seq, fasta)

        if identity > max_iden:
            max_iden = identity
            target = fasta
            if 'ID2' in seen_fastas.columns:
                id2 = seen_fastas.loc[seen_fastas['X2'] == fasta, 'ID2'].values[0]
                if pd.notnull(id2) and id2 != '':
                    target = id2
            if max_iden == 1:
                break

    cached_alignment_score.cache_clear()
    return {'Max. Sequence Identity': max_iden, 'Max. Sequence Identity Target': target}


def get_seen_smiles(family, task):
    if family == 'General':
        family = 'all_families_full'
    else:
        family = TARGET_FAMILY_MAP[family.title()]
    seen_smiles = pd.read_csv(
        f'data/benchmarks/seen_compounds/{family}_{task.lower()}_random_split.csv')
    return seen_smiles


def get_seen_fastas(family, task):
    if family == 'General':
        family = 'all_families_full'
    else:
        family = TARGET_FAMILY_MAP[family.title()]
    seen_fastas = pd.read_csv(
        f'data/benchmarks/seen_targets/{family}_{task.lower()}_random_split.csv')
    return seen_fastas


@cache
def get_fasta_family_map():
    usecols = ['X2', 'ID2', 'Target Family']
    fasta_family_map = pd.concat([
        pd.read_csv('data/target_libraries/ChEMBL33_all_spe_single_prot_info.csv', usecols=usecols),
        pd.read_csv('data/target_libraries/idmapping_not_in_chembl.csv', usecols=usecols)
    ]).drop_duplicates(subset=['X2'], keep='first')
    return fasta_family_map


def lipinski(mol):
    """
    Lipinski's rules:
    Hydrogen bond donors <= 5
    Hydrogen bond acceptors <= 10
    Molecular weight <= 500 daltons
    logP <= 5
    """
    return (
            Lipinski.NumHDonors(mol) <= 5 and
            Lipinski.NumHAcceptors(mol) <= 10 and
            Descriptors.MolWt(mol) <= 500 and
            Crippen.MolLogP(mol) <= 5
    )


def reos(mol):
    """
    Rapid Elimination Of Swill filter:
    Molecular weight between 200 and 500
    LogP between -5.0 and +5.0
    H-bond donor count between 0 and 5
    H-bond acceptor count between 0 and 10
    Formal charge between -2 and +2
    Rotatable bond count between 0 and 8
    Heavy atom count between 15 and 50
    """
    return (
            200 <= Descriptors.MolWt(mol) <= 500 and
            -5.0 <= Crippen.MolLogP(mol) <= 5.0 and
            0 <= Lipinski.NumHDonors(mol) <= 5 and
            0 <= Lipinski.NumHAcceptors(mol) <= 10 and
            -2 <= rdmolops.GetFormalCharge(mol) <= 2 and
            0 <= rdMolDescriptors.CalcNumRotatableBonds(mol) <= 8 and
            15 <= rdMolDescriptors.CalcNumHeavyAtoms(mol) <= 50
    )


def ghose(mol):
    """
    Ghose drug like filter:
    Molecular weight between 160 and 480
    LogP between -0.4 and +5.6
    Atom count between 20 and 70
    Molar refractivity between 40 and 130
    """
    return (
            160 <= Descriptors.MolWt(mol) <= 480 and
            -0.4 <= Crippen.MolLogP(mol) <= 5.6 and
            20 <= rdMolDescriptors.CalcNumAtoms(mol) <= 70 and
            40 <= Crippen.MolMR(mol) <= 130
    )


def veber(mol):
    """
    The Veber filter is a rule of thumb filter for orally active drugs described in
    Veber et al., J Med Chem. 2002; 45(12): 2615-23.:
    Rotatable bonds <= 10
    Topological polar surface area <= 140
    """
    return (
            rdMolDescriptors.CalcNumRotatableBonds(mol) <= 10 and
            rdMolDescriptors.CalcTPSA(mol) <= 140
    )


def rule_of_three(mol):
    """
    Rule of Three filter (Congreve et al., Drug Discov. Today. 8 (19): 876–7, (2003).):
    Molecular weight <= 300
    LogP <= 3
    H-bond donor <= 3
    H-bond acceptor count <= 3
    Rotatable bond count <= 3
    """
    return (
            Descriptors.MolWt(mol) <= 300 and
            Crippen.MolLogP(mol) <= 3 and
            Lipinski.NumHDonors(mol) <= 3 and
            Lipinski.NumHAcceptors(mol) <= 3 and
            rdMolDescriptors.CalcNumRotatableBonds(mol) <= 3
    )


@cache
def load_smarts_patterns(smarts_path):
    # Load the CSV file containing SMARTS patterns
    smarts_df = pd.read_csv(Path(smarts_path))
    # Convert all SMARTS patterns to molecules
    smarts_mols = [Chem.MolFromSmarts(smarts) for smarts in smarts_df['smarts']]
    return smarts_mols


def smarts_filter(mol, smarts_mols):
    for smarts_mol in smarts_mols:
        if smarts_mol is not None and mol.HasSubstructMatch(smarts_mol):
            return False
    return True


def pains(mol):
    smarts_mols = load_smarts_patterns("data/filters/pains.csv")
    return smarts_filter(mol, smarts_mols)


def mlsmr(mol):
    smarts_mols = load_smarts_patterns("data/filters/mlsmr.csv")
    return smarts_filter(mol, smarts_mols)


def dundee(mol):
    smarts_mols = load_smarts_patterns("data/filters/dundee.csv")
    return smarts_filter(mol, smarts_mols)


def glaxo(mol):
    smarts_mols = load_smarts_patterns("data/filters/glaxo.csv")
    return smarts_filter(mol, smarts_mols)


def bms(mol):
    smarts_mols = load_smarts_patterns("data/filters/bms.csv")
    return smarts_filter(mol, smarts_mols)


SCORE_MAP = {
    'SAscore': sascorer.calculateScore,
    'LogP': Crippen.MolLogP,
    'Molecular Weight': Descriptors.MolWt,
    'Number of Atoms': rdMolDescriptors.CalcNumAtoms,
    'Number of Heavy Atoms': rdMolDescriptors.CalcNumHeavyAtoms,
    'Molar Refractivity': Crippen.MolMR,
    'H-Bond Donor Count': Lipinski.NumHDonors,
    'H-Bond Acceptor Count': Lipinski.NumHAcceptors,
    'Rotatable Bond Count': rdMolDescriptors.CalcNumRotatableBonds,
    'Topological Polar Surface Area': rdMolDescriptors.CalcTPSA,
}

FILTER_MAP = {
    # TODO support number_of_violations
    'REOS': reos,
    "Lipinski's Rule of Five": lipinski,
    'Ghose': ghose,
    'Rule of Three': rule_of_three,
    'Veber': veber,
    'PAINS': pains,
    'MLSMR': mlsmr,
    'Dundee': dundee,
    'Glaxo': glaxo,
    'BMS': bms,
}


def validate_columns(df, mandatory_cols):
    missing_cols = [col for col in mandatory_cols if col not in df.columns]
    if missing_cols:
        error_message = (f"The following mandatory columns are missing "
                         f"in the uploaded dataset: {str(mandatory_cols).strip('[]')}.")
        raise ValueError(error_message)
    else:
        return


def process_target_fasta(sequence):
    try:
        if sequence:
            lines = sequence.strip().split("\n")
            if lines[0].startswith(">"):
                lines = lines[1:]
            return ''.join(lines).split(">")[0].strip()
            # record = list(SeqIO.parse(io.StringIO(sequence), "fasta"))[0]
            # return str(record.seq)
        else:
            raise ValueError('Empty FASTA sequence.')
    except Exception as e:
        raise gr.Error(f'Failed to process FASTA due to error: {str(e)}')


def send_email(job_info):
    if job_info.get('email'):
        try:
            email_info = job_info.copy()
            email_serv = os.getenv('EMAIL_SERV')
            email_port = os.getenv('EMAIL_PORT')
            email_addr = os.getenv('EMAIL_ADDR')
            email_pass = os.getenv('EMAIL_PASS')
            email_form = os.getenv('EMAIL_FORM')
            email_subj = os.getenv('EMAIL_SUBJ')

            for key, value in email_info.items():
                if key.endswith("time") and value:
                    email_info[key] = ts_to_str(value, get_timezone_by_ip(email_info['ip']))

            server = smtplib.SMTP(email_serv, int(email_port))
            # server.starttls()

            server.login(email_addr, email_pass)
            msg = MIMEMultipart("alternative")
            msg["From"] = email_addr
            msg["To"] = email_info['email']
            msg["Subject"] = email_subj.format(**email_info)
            msg["Date"] = formatdate(localtime=True)
            msg["Message-ID"] = make_msgid()

            msg.attach(MIMEText(markdown(email_form.format(**email_info)), 'html'))
            msg.attach(MIMEText(email_form.format(**email_info), 'plain'))

            server.sendmail(email_addr, email_info['email'], msg.as_string())
            server.quit()
            gr.Info('Email notification sent.')
        except Exception as e:
            gr.Warning('Failed to send email notification due to error: ' + str(e))


def check_user_running_job(email, request):
    message = ("You already have a running prediction job (ID: {id}) under this {reason}. "
               "Please wait for it to complete before submitting another job.")
    try:
        # with open('jobs.json', 'r') as f:  # /data/
        #     # Load the JSON data from the file
        #     jobs = json.load(f)
        #
        # for job_id, job_info in jobs.items():
        #     # check if a job is running for the email
        #     if email:
        #         if job_info["email"] == email and job_info["status"] == "running":
        #             return message.format(id=job_id, reason="email")
        #     # check if a job is running for the session
        #     elif request.cookies:
        #         for key, value in job_info["cookies"].items() and job_info["status"] == "running":
        #             if key in request.cookies and request.cookies[key] == value:
        #                 return message.format(id=job_id, reason="session")
        #     # check if a job is running for the IP
        #     else:
        #         if job_info["IP"] == request.client.host and job_info["status"] == "running":
        #             return message.format(id=job_id, reason="IP")
        # check if a job is running for the email
        Job = Query()
        if email:
            job = db.search((Job.email == email) & (Job.status == "RUNNING"))
            if job:
                return message.format(id=job[0]['id'], reason="email")
        # check if a job is running for the session
        elif request.cookies:
            for key, value in request.cookies.items():
                job = db.search((Job.cookies[key] == value) & (Job.status == "RUNNING"))
                if job:
                    return message.format(id=job[0]['id'], reason="session")
        # check if a job is running for the IP
        else:
            job = db.search((Job.IP == request.client.host) & (Job.status == "RUNNING"))
            if job:
                return message.format(id=job[0]['id'], reason="IP")

        return False
    except Exception as e:
        raise gr.Error(f'Failed to validate user running jobs due to error: {str(e)}')


def get_timezone_by_ip(ip):
    try:
        data = session.get(f'https://worldtimeapi.org/api/ip/{ip}').json()
        return data['timezone']
    except Exception:
        return 'UTC'


def ts_to_str(timestamp, timezone):
    # Create a timezone-aware datetime object from the UNIX timestamp
    dt = datetime.fromtimestamp(timestamp, pytz.utc)

    # Convert the timezone-aware datetime object to the target timezone
    target_timezone = pytz.timezone(timezone)
    localized_dt = dt.astimezone(target_timezone)

    # Format the datetime object to the specified string format
    return localized_dt.strftime('%Y-%m-%d %H:%M:%S (%Z%z)')


def lookup_job(job_id):
    gr.Info('Start querying the job database...')
    stop = False
    retry = 0
    while not stop:
        try:
            sleep(5)
            Job = Query()
            jobs = db.search((Job.id == job_id))
            if jobs:
                job = jobs[0]
                job_status = job['status']
                job_type = job['type']
                error = job['error']
                start_time = ts_to_str(job['start_time'], get_timezone_by_ip(job['ip']))
                if job.get('end_time'):
                    end_time = ts_to_str(job['end_time'], get_timezone_by_ip(job['ip']))
                if job.get('expiry_time'):
                    expiry_time = ts_to_str(job['expiry_time'], get_timezone_by_ip(job['ip']))
                if job_status == "RUNNING":
                    yield {
                        pred_lookup_status: f'''
Your **{job_type}** job (ID: **{job_id}**) started at 
**{start_time}** and is **RUNNING...**

It might take a few minutes up to a few hours depending on the prediction dataset, the model, and the queue status.
You may keep the page open and wait for job completion, or close the page and revisit later to look up the job status 
using the job id. You will also receive an email notification once the job is done.
''',
                        pred_lookup_btn: gr.Button(visible=False),
                        pred_lookup_stop_btn: gr.Button(visible=True)
                    }
                if job_status == "COMPLETED":
                    stop = True
                    msg = f"Your {job_type} job (ID: {job_id}) has been **COMPLETED**"
                    msg += f" at {end_time}" if job.get('end_time') else ""
                    msg += f" and the results will expire by {expiry_time}." if job.get('expiry_time') else "."
                    msg += f' Redirecting to the report page...'

                    gr.Info(msg)
                    yield {
                        pred_lookup_status: msg,
                        pred_lookup_btn: gr.Button(visible=True),
                        pred_lookup_stop_btn: gr.Button(visible=False),
                        tabs: gr.Tabs(selected='Chemical Property Report'),
                        file_for_report: job['output_file']
                    }
                if job_status == "FAILED":
                    stop = True
                    msg = f'Your {job_type} job (ID: {job_id}) has **FAILED**'
                    msg += f' at {end_time}' if job.get('end_time') else ''
                    msg += f' due to error: {error}.' if job.get('expiry_time') else '.'
                    gr.Info(msg)
                    yield {
                        pred_lookup_status: msg,
                        pred_lookup_btn: gr.Button(visible=True),
                        pred_lookup_stop_btn: gr.Button(visible=False),
                        tabs: gr.Tabs(selected='Prediction Status Lookup'),
                    }
            else:
                stop = (retry > 3)
                if not stop:
                    msg = f'Job ID {job_id} not found. Retrying... ({retry})'
                else:
                    msg = f'Job ID {job_id} not found after {retry} retries. Please check the job ID and try again.'
                gr.Info(msg)
                retry += 1
                yield {
                    pred_lookup_status: msg,
                    pred_lookup_btn: gr.Button(visible=True),
                    pred_lookup_stop_btn: gr.Button(visible=False),
                    tabs: gr.Tabs(selected='Prediction Status Lookup'),
                }

        except Exception as e:
            raise gr.Error(f'Failed to retrieve job status due to error: {str(e)}')


def apply_advanced_opts(prediction_df, opts, df_training):
    # Advanced options for Drug Hit Screening
    if "Calculate Max. Sequence Identity between the Input Target and Targets in the Training Set" in opts:
        x2 = prediction_df['X2'].iloc[0]

        prediction_df[[
            'Max. Sequence Identity to Training Targets',
            'Max. Id. Training Target'
        ]] = pd.Series(max_sequence_identity(x2, df_training))

    if "Calculate Max. Tanimoto Similarity between the Hit Compound and Known Ligands of the Input Target" in opts:
        x2 = prediction_df['X2'].iloc[0]
        pos_compounds_df = df_training.loc[(df_training['X2'] == x2) & (df_training['Y'] == 1)].copy()
        pos_compounds_df['FP'] = pos_compounds_df['X1'].parallel_apply(smiles_to_ecfp)

        @cache
        def max_sim(smiles):
            return max_tanimoto_similarity(smiles, pos_compounds_df)

        prediction_df[[
            'Max. Tanimoto Similarity to Known Ligands',
            'Max. Sim. Ligand'
        ]] = prediction_df['X1'].parallel_apply(max_sim).apply(pd.Series)

        max_sim.cache_clear()

    if "Calculate Max. Sequence Identity between the Input Target and Known Targets of Hit Compound" in opts:
        x2 = prediction_df['X2'].iloc[0]
        prediction_df['X1^'] = prediction_df['X1'].parallel_apply(rdkit_canonicalize)

        @cache
        def max_id(compound):
            pos_targets_df = df_training.loc[df_training['X1'] == compound]
            return max_sequence_identity(x2, pos_targets_df)

        prediction_df[['Max. Sequence Identity to Known Targets of Hit Compound',
                       'Max. Id. Target']] = (
            prediction_df['X1^'].parallel_apply(max_id).apply(pd.Series)
        )
        prediction_df.drop(['X1^'], axis=1, inplace=True)

        max_id.cache_clear()

    # Advanced options for Target Protein Identification
    if "Calculate Max. Tanimoto Similarity between the Input Compound and Compounds in the Training Set" in opts:
        x1 = rdkit_canonicalize(prediction_df['X1'].iloc[0])
        if x1 not in df_training['X1'].values:
            df_training['FP'] = df_training['X1'].parallel_apply(smiles_to_ecfp)

        prediction_df[[
            'Max. Tanimoto Similarity to Training Compounds',
            'Max. Sim. Training Compound'
        ]] = pd.Series(max_tanimoto_similarity(x1, df_training))

    if "Calculate Max. Sequence Identity between the Identified Target and Known Targets of the Input Compound" in opts:
        x1 = rdkit_canonicalize(prediction_df['X1'].iloc[0])
        pos_targets_df = df_training.loc[(df_training['X1'] == x1) & (df_training['Y'] == 1)].copy()

        @cache
        def max_id(fasta):
            return max_sequence_identity(fasta, pos_targets_df)

        prediction_df[[
            'Max. Sequence Identity to Known Targets of Input Compound',
            'Max. Id. Target'
        ]] = prediction_df['X2'].parallel_apply(max_id).apply(pd.Series)

        max_id.cache_clear()

    if "Calculate Max. Tanimoto Similarity between the Input Compound and Known Ligands of the Identified Target" in opts:
        x1 = rdkit_canonicalize(prediction_df['X1'].iloc[0])

        @cache
        def max_sim(fasta):
            pos_targets_df = df_training.loc[(df_training['X2'] == fasta) & (df_training['Y'] == 1)].copy()
            if x1 not in pos_targets_df['X1'].values:
                pos_targets_df['FP'] = pos_targets_df['X1'].apply(smiles_to_ecfp)
            return max_tanimoto_similarity(x1, pos_targets_df)

        prediction_df[[
            'Max. Tanimoto Similarity to Known Ligands of Identified Target',
            'Max. Sim. Ligand'
        ]] = prediction_df['X2'].parallel_apply(max_sim).apply(pd.Series)

        max_sim.cache_clear()

    return prediction_df


def submit_predict(predict_filepath, task, preset, target_family, opts, job_info):
    job_id = job_info['id']
    status = job_info['status']
    send_email(job_info)
    db.insert(job_info)
    error = None
    task_file_abbr = {'Compound-Protein Interaction': 'CPI', 'Compound-Protein Binding Affinity': 'CPA'}
    predictions_file = None
    df_training = pd.read_csv(f'data/complete_{TASK_MAP[task].lower()}_dataset.csv')
    df_training['X1^'] = df_training['X1']
    orig_df = pd.read_csv(predict_filepath)
    alignment_df = get_fasta_family_map()
    prediction_df = pd.DataFrame()

    @cache
    def detect_family(query):
        # Check for an exact match first
        exact_match = alignment_df[alignment_df['X2'] == query]
        if not exact_match.empty:
            row = exact_match.iloc[0]
            return row['Target Family']
        # If no exact match, then calculate alignment score
        else:
            aligner = PairwiseAligner()
            aligner.mode = 'local'

            def align_score(target):
                alignment = aligner.align(query, target)
                return alignment.score / max(len(query), len(target))

            alignment_df['score'] = alignment_df['X2'].apply(align_score)
            row = alignment_df[alignment_df['score'] == alignment_df['score'].max()].iloc[0]
            return row['Target Family']

    if 'Target Family' not in orig_df.columns:
        orig_df['Target Family'] = None
    if orig_df['Target Family'].isna().any():
        orig_df = orig_df.reset_index(drop=True)
        if orig_df['X2'].nunique() > 1:
            orig_df.loc[orig_df['Target Family'].isna(), 'Target Family'] = (
                orig_df.loc[orig_df['Target Family'].isna(), 'X2'].parallel_apply(detect_family)
            )
        else:
            orig_df['Target Family'] = detect_family(orig_df['X2'].iloc[0])
    orig_df['Target Family'] = orig_df['Target Family'].str.capitalize()
    detect_family.cache_clear()

    orig_df['X1^'] = orig_df['X1'].parallel_apply(rdkit_canonicalize)

    orig_df = orig_df.merge(df_training[['X1^', 'X2', 'Y']], on=['X1^', 'X2'], how='left', indicator=False)
    annotated_df = orig_df[~orig_df['Y'].isna()].copy()
    annotated_df.rename(columns={'Y': 'Y^'}, inplace=True)
    annotated_df['Source'] = 'Database'
    columns_to_drop = ['X1^', 'Compound', 'Scaffold', 'Scaffold SMILES']
    columns_to_drop = [col for col in columns_to_drop if col in annotated_df.columns]
    annotated_df.drop(columns_to_drop, axis=1, inplace=True)

    # Save the unannotated data
    unannotated_df = orig_df[orig_df['Y'].isna()].drop(['Y'], axis=1)
    if not unannotated_df.empty:
        unannotated_df.to_csv(predict_filepath, index=False, na_rep='')
    else:
        annotated_df.to_csv(predictions_file, index=False, na_rep='')
        status = "COMPLETED"
        return {run_state: False}

    columns_to_drop = ['ID1', 'X1^', 'Compound', 'Scaffold', 'Scaffold SMILES', 'ID2', 'Y', 'Y^']
    columns_to_drop = [col for col in columns_to_drop if col in orig_df.columns]
    orig_df.drop(columns_to_drop, axis=1, inplace=True)

    try:
        if target_family != 'Family-Specific Auto-Recommendation':
            target_family_value = TARGET_FAMILY_MAP[target_family.title()]
            task_value = TASK_MAP[task]
            preset_value = PRESET_MAP[preset]
            predictions_file = (f'{SERVER_DATA_DIR}/'
                                f'{job_id}_{task_file_abbr[task]}_{preset}_{target_family_value}_predictions.csv')

            cfg = hydra.compose(
                config_name="webserver_inference",
                overrides=[f"task={task_value}",
                           f"preset={preset_value}",
                           f"ckpt_path=resources/checkpoints/{preset_value}-{task_value}-{target_family_value}.ckpt",
                           f"data.data_file='{str(predict_filepath)}'"])

            predictions, _ = predict(cfg)
            predictions = pd.concat([pd.DataFrame(prediction) for prediction in predictions], ignore_index=True)
            predictions['Source'] = f'Predicted ({preset} {target_family})'
            df_list = [prediction_df, predictions]
            prediction_df = pd.concat([df for df in df_list if not df.empty])

        else:
            predictions_file = f'{SERVER_DATA_DIR}/{job_id}_{task_file_abbr[task]}_family-recommended_predictions.csv'
            task_value = TASK_MAP[task]
            score = TASK_METRIC_MAP[task]
            benchmark_df = pd.read_csv(f'data/benchmarks/{task_value}_test_metrics.csv')
            predict_df = pd.read_csv(predict_filepath)

            for family, subset in predict_df.groupby('Target Family'):
                predict_subset_filepath = os.path.join(
                    os.path.dirname(predict_filepath), f'{job_id}_{family}_input.csv'
                )
                subset.to_csv(predict_subset_filepath, index=False, na_rep='')

                seen_compounds = get_seen_smiles(family, task_value)['X1'].values
                if subset['X1^'].iloc[0] in seen_compounds:
                    scenario = "Seen Compound"
                else:
                    scenario = "Unseen Compound"

                filtered_df = benchmark_df[(benchmark_df['Family'] == family.title())
                                           & (benchmark_df['Scenario'] == scenario)
                                           & (benchmark_df['Type'] == 'Family')]

                seen_compounds = get_seen_smiles('General', task_value)['X1'].values
                if subset['X1^'].iloc[0] in seen_compounds:
                    scenario = "Seen Compound"
                else:
                    scenario = "Unseen Compound"

                filtered_df = pd.concat([
                    filtered_df,
                    benchmark_df[(benchmark_df['Family'] == family.title())
                                 & (benchmark_df['Scenario'] == scenario)
                                 & (benchmark_df['Type'] == 'General')]
                ])

                row = filtered_df.loc[filtered_df[score].idxmax()]
                preset_value = PRESET_MAP[row['Model']]
                target_family = TARGET_FAMILY_MAP[family.title()] if row['Type'] == 'Family' else 'general'
                cfg = hydra.compose(
                    config_name="webserver_inference",
                    overrides=[f"task={task_value}",
                               f"preset={preset_value}",
                               f"ckpt_path=resources/checkpoints/{preset_value}-{task_value}-{target_family}.ckpt",
                               f"data.data_file='{str(predict_subset_filepath)}'"])

                predictions, _ = predict(cfg)
                predictions = pd.concat([pd.DataFrame(prediction) for prediction in predictions], ignore_index=True)
                predictions['Source'] = (f'Predicted ({row["Model"]} '
                                         f'{family.title() if row["Type"] == "Family" else "General"})')
                df_list = [prediction_df, predictions]
                prediction_df = pd.concat([df for df in df_list if not df.empty])

        prediction_df = prediction_df.merge(orig_df, on=['X1', 'X2'], how='left', indicator=False)
        df_list = [prediction_df, annotated_df]
        prediction_df = pd.concat([df for df in df_list if not df.empty], ignore_index=True)

        prediction_df = apply_advanced_opts(prediction_df, opts, df_training)

        prediction_df.drop(['N', 'FP'], axis=1, errors='ignore').to_csv(predictions_file, index=False, na_rep='')
        status = 'COMPLETED'

        return {run_state: False}

    except Exception as e:
        gr.Warning(f"Prediction job failed due to error: {str(e)}")
        status = "FAILED"
        predictions_file = None
        error = str(e)
        return {run_state: False}

    finally:
        Job = Query()
        job_query = (Job.id == job_id)

        end_time = time()
        expiry_time = end_time + DB_EXPIRY

        db.update({'end_time': end_time,
                   'expiry_time': expiry_time,
                   'status': status,
                   'error': error,
                   'input_file': predict_filepath,
                   'output_file': predictions_file},
                  job_query)
        if job_info := db.search(job_query)[0]:
            if job_info.get('email'):
                send_email(job_info)


def update_df(file, progress=gr.Progress(track_tqdm=True)):
    if file and Path(file).is_file():
        task = None
        job = None

        if "_CPI_" in str(file):
            task = 'Compound-Protein Interaction'
        elif "_CPA_" in str(file):
            task = 'Compound-Protein Binding Affinity'

        df = pd.read_csv(file)

        if 'N' in df.columns:
            df.set_index('N', inplace=True)

        if not any(col in ['X1', 'X2'] for col in df.columns):
            gr.Warning("At least one of columns `X1` and `X2` must be in the uploaded dataset.")
            return {analyze_btn: gr.Button(interactive=False)}

        if 'X1' in df.columns:
            if 'Compound' not in df.columns or df['Compound'].dtype != 'object':
                df['Compound'] = df['X1'].parallel_apply(
                    lambda smiles: PandasTools._MolPlusFingerprint(Chem.MolFromSmiles(smiles)))
            df['Scaffold'] = df['Compound'].parallel_apply(MurckoScaffold.GetScaffoldForMol)
            df['Scaffold SMILES'] = df['Scaffold'].parallel_apply(lambda x: Chem.MolToSmiles(x))
            df['Pharmacophore'] = None
        if task == 'Compound-Protein Binding Affinity':
            # Convert Y^ from pIC50 (nM) to IC50 (nM)
            if 'Y^' in df.columns:
                df['Y^'] = 10 ** (-df['Y^']) * 1e9

        n_compound = df['X1'].nunique()
        n_protein = df['X2'].nunique()

        if n_compound == 1 and n_protein >= 2:
            job = 'Target Protein Identification'
            if task == 'Compound-Protein Interaction':
                opts = TARGET_IDENTIFY_CPI_OPTS
            elif task == 'Compound-Protein Binding Affinity':
                opts = TARGET_IDENTIFY_CPA_OPTS
        if n_compound >= 2 and n_protein == 1:
            job = 'Drug Hit Screening'
            if task == 'Compound-Protein Interaction':
                opts = DRUG_SCRENN_CPI_OPTS
            elif task == 'Compound-Protein Binding Affinity':
                opts = DRUG_SCRENN_CPA_OPTS

        return {
            html_report: create_html_report(df, file=None, task=task),
            raw_df: df,
            report_df: df.copy(),
            analyze_btn: gr.Button(interactive=True),
            report_task: task,
            job_opts: gr.CheckboxGroup(
                label=f'{job} Advanced Options',
                choices=opts, visible=True
            ) if job else gr.CheckboxGroup(visible=False),
        }
    else:
        return {analyze_btn: gr.Button(interactive=False)}


def create_html_report(df, file=None, task=None, opts=(), progress=gr.Progress(track_tqdm=True)):
    df_html = df.copy(deep=True)
    column_aliases = COLUMN_ALIASES.copy()
    cols_left = list(pd.Index([
        'ID1', 'ID2', 'Compound', 'Scaffold', 'Pharmacophore', 'X1', 'Scaffold SMILES', 'X2', 'Y^'
    ]).intersection(df_html.columns))
    # cols_right = list(pd.Index(['X1', 'X2']).intersection(df_html.columns))
    # df_html = df_html[cols_left + (df_html.columns.drop(cols_left + cols_right).tolist()) + cols_right]
    df_html = df_html[cols_left + df_html.columns.drop(cols_left).tolist()]

    if isinstance(task, str):
        column_aliases.update({
            'Y^': 'Interaction Probability' if task == 'Compound-Protein Interaction'
            else 'Binding Affinity (IC50 [nM])'
        })

    ascending = True if column_aliases['Y^'] == 'Binding Affinity (IC50 [nM])' else False
    df_html = df_html.sort_values(
        [col for col in ['Y^'] if col in df_html.columns], ascending=ascending
    )

    if not file:
        df_html = df_html.iloc[:31]

    # Remove repeated info for one-against-N tasks to save visual and physical space
    job = 'Chemical Property'
    unique_entity = 'Unique Entity'
    unique_df = None
    category = None
    columns_unique = None

    if 'Exclude Pharmacophore 3D' not in opts:
        df_html['Pharmacophore'] = df_html['Compound'].parallel_apply(
            lambda x: mol_to_pharm3d(x) if not pd.isna(x) else x)

    if 'Compound' in df_html.columns and 'Exclude Molecular Graph' not in opts:
        df_html['Compound'] = df_html['Compound'].parallel_apply(
            lambda x: PandasTools.PrintAsImageString(x) if not pd.isna(x) else x)
    else:
        df_html.drop(['Compound'], axis=1, inplace=True)

    if 'Scaffold' in df_html.columns and 'Exclude Scaffold Graph' not in opts:
        df_html['Scaffold'] = df_html['Scaffold'].parallel_apply(
            lambda x: PandasTools.PrintAsImageString(x) if not pd.isna(x) else x)
    else:
        df_html.drop(['Scaffold'], axis=1, inplace=True)

    if 'X1' in df_html.columns and 'X2' in df_html.columns:
        n_compound = df_html['X1'].nunique()
        n_protein = df_html['X2'].nunique()

        if n_compound == 1 and n_protein >= 2:
            unique_entity = 'Compound of Interest'
            if any(col in df_html.columns for col in ['Y^', 'Y']):
                job = 'Target Protein Identification'
                category = 'Target Family'
            columns_unique = df_html.columns.isin(
                ['ID1', 'Compound', 'Scaffold', 'X1', 'Scaffold SMILES', 'Pharmacophore',
                 'Max. Tanimoto Similarity to Training Compounds', 'Max. Sim. Training Compound']
                + list(FILTER_MAP.keys()) + list(SCORE_MAP.keys())
            )

        elif n_compound >= 2 and n_protein == 1:
            unique_entity = 'Target of Interest'
            if any(col in df_html.columns for col in ['Y^', 'Y']):
                job = 'Drug Hit Screening'
                category = 'Scaffold SMILES'
            columns_unique = df_html.columns.isin(
                ['X2', 'ID2', 'Target Family',
                 'Max. Sequence Identity to Training Targets', 'Max. Id. Training Target']
            )

        elif 'Y^' in df_html.columns:
            job = 'Interaction Pair Inference'

    df_html.rename(columns=column_aliases, inplace=True)
    df_html.index.name = 'Index'
    if 'Target FASTA' in df_html.columns:
        df_html['Target FASTA'] = df_html['Target FASTA'].parallel_apply(
            lambda x: wrap_text(x) if not pd.isna(x) else x)

    num_cols = df_html.select_dtypes('number').columns
    num_col_colors = sns.color_palette('husl', len(num_cols))
    bool_cols = df_html.select_dtypes(bool).columns
    bool_col_colors = {True: 'lightgreen', False: 'lightpink'}

    if columns_unique is not None:
        unique_df = df_html.loc[:, columns_unique].iloc[[0]].copy()
        df_html = df_html.loc[:, ~columns_unique]
        df_html.dropna(how='all', axis=1, inplace=True)
        unique_df.dropna(how='all', axis=1, inplace=True)

    if not file:
        if 'Compound ID' in df_html.columns:
            df_html.drop(['Compound SMILES'], axis=1, inplace=True)
        if 'Target ID' in df_html.columns:
            df_html.drop(['Target FASTA'], axis=1, inplace=True)
        if 'Target FASTA' in df_html.columns:
            df_html['Target FASTA'] = df_html['Target FASTA'].parallel_apply(
                lambda x: wrap_text(x) if not pd.isna(x) else x)
        if 'Scaffold SMILES' in df_html.columns:
            df_html.drop(['Scaffold SMILES'], axis=1, inplace=True)

        # FIXME: Temporarily drop pharmacophore column before an image solution is found
        if 'Pharmacophore' in df_html.columns:
            df_html.drop(['Pharmacophore'], axis=1, inplace=True)
        if unique_df is not None and 'Pharmacophore' in unique_df.columns:
            unique_df.drop(['Pharmacophore'], axis=1, inplace=True)

        styled_df = df_html.fillna('').style.format(precision=3)

        for i, col in enumerate(num_cols):
            cmap = sns.light_palette(num_col_colors[i], as_cmap=True)
            if col in df_html.columns:
                if col not in ['Binding Affinity (IC50 [nM])']:
                    cmap.set_bad('white')
                    styled_df = styled_df.background_gradient(
                        subset=[col], cmap=cmap)
                else:
                    cmap = cmap.reversed()
                    cmap.set_bad('white')
                    styled_df = styled_df.background_gradient(
                        subset=[col], cmap=cmap)

        if any(df_html.columns.isin(bool_cols)):
            styled_df.applymap(lambda val: f'background-color: {bool_col_colors[val]}', subset=bool_cols)

        table_html = styled_df.to_html()
        unique_html = ''
        if unique_df is not None:
            if 'Target FASTA' in unique_df.columns:
                unique_df['Target FASTA'] = unique_df['Target FASTA'].str.replace('\n', '<br>')

            if 'Max. Sequence Identity to Training Targets' in unique_df.columns:
                # Add alert emoji for sequence identity below 0.85
                if unique_df['Max. Sequence Identity to Training Targets'].iloc[0] < 0.85:
                    unique_df['Max. Sequence Identity to Training Targets'] = (
                        unique_df['Max. Sequence Identity to Training Targets'].apply(
                            lambda x: f'<span style="color: red;">{x:.3f}'
                                      f' ⚠️Lower than recommended (0.85)'
                                      f' - predictive reliability may be compromised</span>'
                        )
                    )

            if 'Max. Tanimoto Similarity to Training Compounds' in unique_df.columns:
                # Add alert emoji for sequence identity below 0.85
                if unique_df['Max. Tanimoto Similarity to Training Compounds'].iloc[0] < 0.85:
                    unique_df['Max. Tanimoto Similarity to Training Compounds'] = (
                        unique_df['Max. Tanimoto Similarity to Training Compounds'].apply(
                            lambda x: f'<span style="color: red;">{x:.3f}'
                                      f' ⚠️Lower than recommended (0.85)'
                                      f' - predictive reliability may be compromised</span>'
                        )
                    )

            if any(unique_df.columns.isin(bool_cols)):
                unique_df = unique_df.style.applymap(
                    lambda val: f"background-color: {bool_col_colors[val]}", subset=bool_cols)
            unique_html = (f'<div style="font-family: Courier !important;">'
                           f'{unique_df.to_html(escape=False, index=False)}</div>')

        return (f'<div style="font-size: 16px; font-weight: bold;">{job} Report Preview (Top 30 Records)</div>'
                f'<div style="overflow-x:auto; font-family: Courier !important;">{unique_html}</div>'
                f'<div style="overflow:auto; height: 300px; font-family: Courier !important;">{table_html}</div>')

    else:
        image_zoom_formatter = HTMLTemplateFormatter(template='<div class="image-zoom-viewer"><%= value %></div>')
        uniprot_id_formatter = HTMLTemplateFormatter(
            template='<% if (value == value) { '  # Check if value is not NaN
                     'if (/^[OPQ][0-9][A-Z0-9]{3}[0-9]|[A-NR-Z][0-9]([A-Z][A-Z0-9]{2}[0-9]){1,2}$/.test(value)) '
            # Check if value is a valid UniProt ID
                     '{ %><a href="https://www.uniprot.org/uniprotkb/<%= value %>" target="_blank"><%= value %></a><% '
            # Else treat it as a sequence or other plain-text string, line-warping every 60 characters
                     '} else { %><div style="white-space: pre-wrap;"><%= value.match(/.{1,60}/g).join("<br>") '
                     '%></div><% } %><% } else { %><% } %>'  # Output empty string if value is NaN
        )
        pubchem_id_formatter = HTMLTemplateFormatter(
            template='<% if (value == value) { '  # Check if value is not NaN
                     '%><a href="https://pubchem.ncbi.nlm.nih.gov/#query=<%= value %>" '
                     'target="_blank"><%= value %></a>'
                     '<% } else { %><% } %>'  # Output empty string if value is NaN
        )
        alert_emoji_formatter = HTMLTemplateFormatter(
            template='<% if (value < 0.85) { '
                     '%><span style="color: red;"><%= value %> '
                     '⚠️Lower than recommended (0.85) - predictive reliability may be compromised</span><% '
                     '} else { %><%= value %><% } %>'
        )
        bool_formatters = {col: BooleanFormatter() for col in bool_cols}
        float_formatters = {col: NumberFormatter(format='0.000') for col in df_html.select_dtypes('floating').columns}
        other_formatters = {
            'Interaction Probability': {'type': 'progress', 'max': 1.0, 'legend': True},
            'Compound': image_zoom_formatter,
            'Scaffold': image_zoom_formatter,
            'Pharmacophore': {'type': 'executeScriptFormatter'},
            'Target FASTA': {'type': 'textarea', 'width': 60},
            'Target ID': uniprot_id_formatter,
            'Compound ID': pubchem_id_formatter,
            'Max. Sim. Ligand': pubchem_id_formatter,
            'Max. Id. Target': uniprot_id_formatter,
            'Max. Sim. Training Compound': pubchem_id_formatter,
            'Max. Id. Training Target': uniprot_id_formatter,
            'Max. Sequence Identity to Training Targets': alert_emoji_formatter,
            'Max. Sequence Identity to Known Targets of Hit Compound': alert_emoji_formatter,
        }
        formatters = {**bool_formatters, **float_formatters, **other_formatters}

        # html = df.to_html(file)
        # return html

        report_table = pn.widgets.Tabulator(
            df_html, formatters=formatters,
            frozen_columns=[
                'Index', 'Target ID', 'Compound ID', 'Compound'
            ],
            disabled=True, sizing_mode='stretch_both', pagination='local', page_size=10
        )

        for i, col in enumerate(num_cols):
            cmap = sns.light_palette(num_col_colors[i], as_cmap=True)
            if col not in ['Binding Affinity (IC50 [nM])']:
                if col not in ['Interaction Probability']:
                    cmap.set_bad(color='white')
                    report_table.style.background_gradient(
                        subset=df_html.columns == col, cmap=cmap)
                else:
                    continue
            else:
                cmap = cmap.reversed()
                cmap.set_bad(color='white')
                report_table.style.background_gradient(
                    subset=df_html.columns == col, cmap=cmap)

        pie_charts = {}
        for y in df_html.columns.intersection(['Interaction Probability', 'Binding Affinity (IC50 [nM])']):
            pie_charts[y] = []
            for k in [10, 30, 100]:
                if k < len(df_html):
                    pie_charts[y].append(create_pie_chart(df_html, category=category, value=y, top_k=k))
            pie_charts[y].append(create_pie_chart(df_html, category=category, value=y, top_k=len(df_html)))

        # Remove keys with empty values
        pie_charts = {k: v for k, v in pie_charts.items() if any(v)}

        panel_css = """
            .tabulator {
                font-family: Courier New !important;
                font-weight: normal !important;
                font-size: 12px !important;
            }
            
            .tabulator-cell {
                overflow: visible !important;
                align-content: center !important;
            }
            
            .tabulator-cell:hover {
                z-index: 1000 !important;
            }
            
            .image-zoom-viewer {
                display: inline-block;
                overflow: visible;
                z-index: 1000;
            }
            
            .image-zoom-viewer::after {
                content: "";
                top: 0;
                left: 0;
                width: 100%;
                height: 100%;
                pointer-events: none;
            }
            
            .image-zoom-viewer:hover::after {
                pointer-events: all;
            }
            
            /* When hovering over the container, scale its child (the SVG) */
            .tabulator-cell:hover .image-zoom-viewer svg {
                padding: 3px;
                position: absolute;
                background-color: rgba(250, 250, 250, 0.854);
                box-shadow: 0 0 10px rgba(0, 0, 0, 0.618);
                border-radius: 3px;
                transform: scale(3); /* Scale up the SVG */
                transition: transform 0.3s ease;
                pointer-events: none; /* Prevents the SVG from blocking mouse interactions */
                z-index: 1000;
            }
        """

        pn.extension(
            raw_css=[panel_css],
            js_files={'panel_custom': 'static/panel.js', '3Dmol': 'static/3Dmol-min.js'},
            # js_modules={'3Dmol': 'static/3Dmol-min.js'},
            inline=True,
        )

        template = pn.template.VanillaTemplate(
            title=f'DeepSEQreen {job} Report',
            sidebar=[],
            favicon='deepseqreen.ico',
            logo='deepseqreen.svg',
            header_background='#F3F5F7',
            header_color='#4372c4',
            busy_indicator=None,
        )

        stats_pane = pn.Row()
        if unique_df is not None:
            unique_table = pn.widgets.Tabulator(unique_df, formatters=formatters, sizing_mode='stretch_width',
                                                show_index=False, disabled=True,
                                                frozen_columns=['Compound ID', 'Compound', 'Target ID'])
            # if pie_charts:
            #     unique_table.width = 640
            stats_pane.append(pn.Column(f'### {unique_entity}', unique_table))
        if pie_charts:
            for score_name, figure_list in pie_charts.items():
                stats_pane.append(
                    pn.Column(f'### {category} by Top {score_name}',
                              pn.Tabs(*figure_list, tabs_location='above'))
                    # pn.Card(pn.Row(v), title=f'{category} by Top {k}')
                )

        if stats_pane:
            template.main.append(pn.Card(stats_pane,
                                         sizing_mode='stretch_width', title='Summary Statistics', margin=10))

        template.main.append(
            pn.Card(report_table, title=f'{job} Results',  # width=1200,
                    margin=10)
        )

        template.save(file, title=f'DeepSEQreen {job} Report', resources=INLINE)
        return file


def create_pie_chart(df, category, value, top_k):
    if category not in df or value not in df:
        return
    top_k_df = df.nlargest(top_k, value)
    category_counts = top_k_df[category].value_counts()
    data = pd.DataFrame({category: category_counts.index, 'value': category_counts.values})

    data['proportion'] = data['value'] / data['value'].sum()
    # Merge rows with proportion less than 0.2% into one row
    mask = data['proportion'] < 0.002
    if any(mask):
        merged_row = data[mask].sum()
        merged_row[category] = '...'
        data = pd.concat([data[~mask], pd.DataFrame(merged_row).T])
    data['angle'] = data['proportion'] * 2 * pi

    color_dict = {cat: color for cat, color in
                  zip(df[category].unique(),
                      (Category20c_20 * (len(df[category].unique()) // 20 + 1))[:len(df[category].unique())])}
    color_dict['...'] = '#636363'
    data['color'] = data[category].map(color_dict)

    tooltips = [
        (f"{category}", f"@{{{category}}}"),
        ("Count", "@value"),
        ("Percentage", "@proportion{0.0%}")
    ]

    if category == 'Scaffold SMILES' and 'Scaffold' in df.columns:
        data = data.merge(top_k_df[['Scaffold SMILES', 'Scaffold']].drop_duplicates(), how='left',
                          left_on='Scaffold SMILES', right_on='Scaffold SMILES')
        tooltips.append(("Scaffold", "<div>@{Scaffold}{safe}</div>"))
    p = figure(height=384, width=960, name=f"Top {top_k}" if top_k < len(df) else 'All', sizing_mode='stretch_height',
               toolbar_location=None, tools="hover", tooltips=tooltips, x_range=(-0.4, 0.4))

    def truncate_label(label, max_length=60):
        return label if len(label) <= max_length else label[:max_length] + "..."

    data['legend_field'] = data[category].apply(truncate_label)

    p.add_layout(Legend(padding=0, margin=0), 'right')
    p.wedge(x=0, y=1, radius=0.3,
            start_angle=cumsum('angle', include_zero=True), end_angle=cumsum('angle'),
            line_color="white", fill_color='color', legend_field='legend_field', source=data)

    # Limit the number of legend items to 20 and add "..." if there are more than 20 items
    if len(p.legend.items) > 20:
        new_legend_items = p.legend.items[:20]
        new_legend_items.append(LegendItem(label="..."))
        p.legend.items = new_legend_items

    p.legend.label_text_font_size = "10pt"
    p.legend.label_text_font = "courier"
    p.axis.axis_label = None
    p.axis.visible = False
    p.grid.grid_line_color = None
    p.outline_line_width = 0
    p.min_border = 0
    p.margin = 0

    return p


def submit_report(df, score_list, filter_list, opt_list, task, progress=gr.Progress(track_tqdm=True)):
    df_report = df.copy()
    try:
        for filter_name in filter_list:
            df_report[filter_name] = df_report['Compound'].parallel_apply(
                lambda x: FILTER_MAP[filter_name](x) if not pd.isna(x) else x)

        for score_name in score_list:
            df_report[score_name] = df_report['Compound'].parallel_apply(
                lambda x: SCORE_MAP[score_name](x) if not pd.isna(x) else x)

        if opt_list:
            df_training = pd.read_csv(f'data/complete_{TASK_MAP[task].lower()}_dataset.csv')
            df_report = apply_advanced_opts(df_report, opt_list, df_training)

        return (create_html_report(df_report, file=None, task=task), df_report,
                gr.File(visible=False), gr.File(visible=False))

    except Exception as e:
        gr.Warning(f'Failed to report results due to error: {str(e)}')
        return None, None, None, None


def wrap_text(text, line_length=60):
    if isinstance(text, str):
        wrapper = textwrap.TextWrapper(width=line_length)
        if text.startswith('>'):
            sections = text.split('>')
            wrapped_sections = []
            for section in sections:
                if not section:
                    continue
                lines = section.split('\n')
                seq_header = lines[0]
                wrapped_seq = wrapper.fill(''.join(lines[1:]))
                wrapped_sections.append(f">{seq_header}\n{wrapped_seq}")
            return '\n'.join(wrapped_sections)
        else:
            return wrapper.fill(text)
    else:
        return text


def unwrap_text(text):
    return text.strip.replece('\n', '')


def drug_library_from_sdf(sdf_path):
    return PandasTools.LoadSDF(
        sdf_path,
        smilesName='X1', molColName='Compound', includeFingerprints=True
    )


def process_target_library_upload(library_upload):
    if library_upload.endswith('.csv'):
        df = pd.read_csv(library_upload)
    elif library_upload.endswith('.fasta'):
        df = target_library_from_fasta(library_upload)
    else:
        raise gr.Error('Currently only CSV and FASTA files are supported as target libraries.')
    validate_columns(df, ['X2'])
    return df


def process_drug_library_upload(library_upload):
    if library_upload.endswith('.csv'):
        df = pd.read_csv(library_upload)
    elif library_upload.endswith('.sdf'):
        df = drug_library_from_sdf(library_upload)
    else:
        raise gr.Error('Currently only CSV and SDF files are supported as drug libraries.')
    validate_columns(df, ['X1'])
    return df


def target_library_from_fasta(fasta_path):
    records = list(SeqIO.parse(fasta_path, "fasta"))
    id2 = [record.id for record in records]
    seq = [str(record.seq) for record in records]
    df = pd.DataFrame({'ID2': id2, 'X2': seq})
    return df


theme = gr.themes.Base(spacing_size="sm", text_size='md', font=gr.themes.GoogleFont("Roboto")).set(
    background_fill_primary='#eef3f9',
    background_fill_secondary='white',
    checkbox_label_background_fill='#eef3f9',
    checkbox_label_background_fill_hover='#dfe6f0',
    checkbox_background_color='white',
    checkbox_border_color='#4372c4',
    border_color_primary='#4372c4',
    border_color_accent='#2e6ab5',
    button_primary_background_fill='#2e6ab4',
    button_primary_text_color='white',
    body_text_color='#28496F',
    block_background_fill='#fbfcfd',
    block_title_text_color='#28496F',
    block_label_text_color='#28496F',
    block_info_text_color='#505358',
    block_border_color=None,
    # input_border_color='#4372c4',
    # panel_border_color='#4372c4',
    input_background_fill='#F1F2F4',
)

with gr.Blocks(theme=theme, title='DeepSEQreen', css=CSS, delete_cache=(3600, 48 * 3600)) as demo:
    run_state = gr.State(value=False)
    screen_flag = gr.State(value=False)
    identify_flag = gr.State(value=False)
    infer_flag = gr.State(value=False)

    with gr.Tabs() as tabs:
        with gr.TabItem(label='Drug Hit Screening', id='Drug Hit Screening'):
            gr.Markdown('''
            # <center>Drug Hit Screening</center>
            
            <center>
            To predict interactions or binding affinities of a single target against a compound library.
            </center>
            ''')
            with gr.Row():
                with gr.Column():
                    HelpTip(
                        "Enter (paste) a amino acid sequence below manually or upload a FASTA file. "
                        "If multiple entities are in the FASTA, only the first will be used. "
                        "Alternatively, enter a Uniprot ID or gene symbol with organism and click Query for "
                        "the sequence."
                    )
                    target_input_type = gr.Dropdown(
                        label='Step 1. Select Target Input Type and Input',
                        choices=['Sequence', 'UniProt ID', 'Gene symbol'],
                        info='Enter (paste) a FASTA string below manually or upload a FASTA file.',
                        value='Sequence',
                        scale=4, interactive=True
                    )

            with gr.Row():
                target_id = gr.Textbox(show_label=False, visible=False,
                                       interactive=True, scale=4,
                                       info='Enter a UniProt ID and query.')
                target_gene = gr.Textbox(
                    show_label=False, visible=False,
                    interactive=True, scale=4,
                    info='Enter a gene symbol and query. The first record will be used.')
                target_organism = gr.Textbox(
                    info='Organism scientific name (default: Homo sapiens).',
                    placeholder='Homo sapiens', show_label=False,
                    visible=False, interactive=True, scale=4, )
                target_upload_btn = gr.UploadButton(label='Upload a FASTA File', type='binary',
                                                    visible=True, variant='primary',
                                                    size='lg')
                target_paste_markdown = gr.Button(value='OR Paste Your Sequence Below',
                                                  variant='secondary')
                target_query_btn = gr.Button(value='Query the Sequence', variant='primary',
                                             visible=False, scale=4)
            # with gr.Row():
            #     example_uniprot = gr.Button(value='Example: Q16539', elem_classes='example', visible=False)
            #     example_gene = gr.Button(value='Example: MAPK14', elem_classes='example', visible=False)
            example_fasta = gr.Button(value='Example: MAPK14 (Q16539)', elem_classes='example')
            target_fasta = gr.Code(label='Input or Display FASTA', interactive=True, lines=5)
            # with gr.Row():
            #     with gr.Column():
            # with gr.Column():
            #     gr.File(label='Example FASTA file',
            #             value='data/examples/MAPK14.fasta', interactive=False)

            with gr.Row():
                with gr.Column(min_width=200):
                    HelpTip(
                        "Click Auto-detect to identify the protein family using sequence alignment. "
                        "This optional step allows applying a family-specific model instead of a all-family "
                        "model (general). "
                        "Manually select general if the alignment results are unsatisfactory."
                    )
                    drug_screen_target_family = gr.Dropdown(
                        choices=list(TARGET_FAMILY_MAP.keys()),
                        value='General',
                        label='Step 2. Select Target Family (Optional)', interactive=True)
                    target_family_detect_btn = gr.Button(value='OR Let Us Auto-Detect for You',
                                                         variant='primary')
                with gr.Column(min_width=200):
                    HelpTip(
                        "Interaction prediction provides you binding probability score between the target of "
                        "interest and each compound in the library, "
                        "while affinity prediction directly estimates their binding strength measured using "
                        "half maximal inhibitory concentration (IC<sub>50</sub>) in units of nM."
                    )
                    drug_screen_task = gr.Dropdown(
                        list(TASK_MAP.keys()),
                        label='Step 3. Select a Prediction Task',
                        value='Compound-Protein Interaction')
                with gr.Column(min_width=200):
                    HelpTip(
                        "Select your preferred model, or click Recommend for the best-performing model based "
                        "on the selected task, family, and whether the target was trained. "
                        "Please refer to documentation for detailed benchmark results."
                    )
                    drug_screen_preset = gr.Dropdown(
                        list(PRESET_MAP.keys()),
                        label='Step 4. Select a Preset Model')
                    screen_preset_recommend_btn = gr.Button(
                        value='OR Let Us Recommend for You', variant='primary')

            with gr.Row():
                with gr.Column():
                    HelpTip(
                        "Select a preset compound library (e.g., DrugBank). "
                        "Alternatively, upload a CSV file with a column named X1 containing compound SMILES, "
                        "or use an SDF file (Max. 10,000 compounds per task). Example CSV and SDF files are "
                        "provided below and can be downloaded by clicking the lower right corner."
                    )
                    drug_library = gr.Dropdown(
                        label='Step 5. Select a Preset Compound Library',
                        choices=list(DRUG_LIBRARY_MAP.keys()))
                    with gr.Row():
                        gr.File(label='Example SDF compound library',
                                value='data/examples/compound_library.sdf', interactive=False)
                        gr.File(label='Example CSV compound library',
                                value='data/examples/compound_library.csv', interactive=False)
                    drug_library_upload_btn = gr.UploadButton(
                        label='OR Upload Your Own Library', variant='primary')
                    drug_library_upload = gr.File(label='Custom compound library file', visible=False)

                with gr.Column():
                    HelpTip("""
<b>Max. Sequence Identity between the Input Target and Targets in the Training Set</b>: 
this serves as an indicator of the predictioon applicability/reliability – 
higher similarities indicate more reliable predictions (preferably > 0.85).<br>
<b>Max. Tanimoto Similarity between the Hit Compound and Known Ligands of the Input Target</b>: 
this serves as an indicator of both the confidence level and novelty of the predicted hit compounds – 
higher similarities suggest greater confidence, while lower Tanimoto similarities may indicate the novelty 
of the identified hit compounds compared to known drugs or true interacting compounds of the input target.<br>
<b>Max. Sequence Identity between the Input Target and Known Targets of Hit Compound</b>: 
this serves as an additional indicator of the confidence level of the predicted hit compounds – 
higher identities usually lead to greater confidence in the predictions.<br>
""")
                    drug_screen_opts = gr.CheckboxGroup(
                        label="Step 6. Select Advanced Options",
                        value=DRUG_SCRENN_CPI_OPTS[0],
                        choices=DRUG_SCRENN_CPI_OPTS,
                        info="Advanced features - may increase the job computation time. "
                             "See the Help Tip on the right or the Documentation for detailed explanation.",

                    )
            with gr.Row():
                with gr.Column():
                    drug_screen_email = gr.Textbox(
                        label='Step 7. Input Your Email Address (Optional)',
                        info="Your email address will be used to notify you of the status of your job. "
                             "If you cannot receive the email, please check your spam/junk folder."
                    )

            with gr.Row(visible=True):
                with gr.Row():
                    drug_screen_clr_btn = gr.ClearButton(size='lg')
                    drug_screen_btn = gr.Button(value='SUBMIT THE SCREENING JOB', variant='primary', size='lg')

        screen_data_for_predict = gr.File(visible=False, file_count="single", type='filepath')

        with gr.TabItem(label='Target Protein Identification', id='Target Protein Identification'):
            gr.Markdown('''
            # <center>Target Protein Identification</center>
            
            <center>
            To predict interactions or binding affinities of a single compound against a protein library.
            </center>
            ''')
            with gr.Column() as identify_page:
                with gr.Row():
                    with gr.Column():
                        HelpTip(
                            "Enter (paste) a compound SMILES below manually or upload a SDF file. "
                            "If multiple entities are in the SDF, only the first will be used. "
                            "SMILES can be obtained by searching for the compound of interest in databases such "
                            "as NCBI, PubChem and and ChEMBL."
                        )
                        compound_type = gr.Dropdown(
                            label='Step 1. Select Compound Input Type and Input',
                            choices=['SMILES', 'SDF'],
                            info='Enter (paste) an SMILES string or upload an SDF file to convert to SMILES.',
                            value='SMILES',
                            interactive=True)
                        compound_upload_btn = gr.UploadButton(
                            label='OR Upload a SDF File', variant='primary', type='binary', visible=False)

                compound_smiles = gr.Code(label='Input or Display Compound SMILES', interactive=True, lines=5)
                example_drug = gr.Button(value='Example: Aspirin', elem_classes='example')

                with gr.Row():
                    with gr.Column(visible=True):
                        HelpTip(
                            "By default, models trained on all protein families (general) will be applied. "
                            "If you upload a target library containing proteins all in the same family, "
                            "you may manually select a Target Family."
                        )
                        # target_identify_target_family = gr.Dropdown(
                        #     choices=['Family-Specific Auto-Recommendation'] + list(TARGET_FAMILY_MAP.keys()),
                        #     value='Family-Specific Auto-Recommendation',
                        #     label='Step 2. Select Target Family')
                        target_identify_target_family = gr.Dropdown(
                            choices=['General'],
                            value='General',
                            label='Step 2. Select Target Family')
                    with gr.Column():
                        HelpTip(
                            "Interaction prediction provides you binding probability score between the target of "
                            "interest and each compound in the library, while affinity prediction directly "
                            "estimates their binding strength measured using "
                            "half maximal inhibitory concentration (IC<sub>50</sub>) in units of nM."
                        )
                        target_identify_task = gr.Dropdown(
                            list(TASK_MAP.keys()),
                            label='Step 3. Select a Prediction Task',
                            value='Compound-Protein Interaction')

                    with gr.Column():
                        HelpTip(
                            "Select your preferred model, or click Recommend for the best-performing model based "
                            "on the selected task and whether the compound was trained. By default, General-trained "
                            "model is used for Target Protein Identification. "
                            "Please refer to the documentation for detailed benchmark results."
                        )
                        # target_identify_preset = gr.Dropdown(
                        #     choices=['Family-Specific Auto-Recommendation'] + list(PRESET_MAP.keys()),
                        #     value='Family-Specific Auto-Recommendation',
                        #     label='Step 4. Select a Preset Model')
                        target_identify_preset = gr.Dropdown(
                            choices=['DeepConvDTI', 'DeepDTA', 'DrugVQA-Seq', 'DrugBAN', 'HyperAttentionDTI', 'MGraphDTA'],
                            value='DrugBAN',
                            label='Step 4. Select a Preset Model')
                        identify_preset_recommend_btn = gr.Button(value='OR Let Us Recommend for You',
                                                                  variant='primary')
                with gr.Row():
                    with gr.Column():
                        HelpTip(
                            "Select a preset target library (e.g., ChEMBL33_human_proteins). "
                            "Alternatively, upload a CSV file with a column named X2 containing target protein "
                            "sequences, or use an FASTA file (Max. 10,000 targets per task). "
                            "Example CSV and SDF files are provided below "
                            "and can be downloaded by clicking the lower right corner."
                        )
                        target_library = gr.Dropdown(
                            label='Step 5. Select a Preset Target Library',
                            choices=list(TARGET_LIBRARY_MAP.keys()))
                        with gr.Row():
                            gr.File(label='Example FASTA target library',
                                    value='data/examples/target_library.fasta', interactive=False)
                            gr.File(label='Example CSV target library',
                                    value='data/examples/target_library.csv', interactive=False)
                        target_library_upload_btn = gr.UploadButton(
                            label='OR Upload Your Own Library', variant='primary')
                        target_library_upload = gr.File(label='Custom target library file', visible=False)
                    with gr.Column():
                        HelpTip("""
<b>Max. Tanimoto Similarity between the Input Compound and Compounds in the Training Set</b>:
this serves as an indicator of prediction applicability and reliability –
higher similarities indicates more reliable predictions (ideally > 0.85).<br>
<b>Max. Sequence Identity between the Identified Target and Known Targets of the Input Compound</b>:
this serves as an indicator of prediction confidence for the potential targets –
higher similarities typically imply higher confidence levels.<br>
<b>Max. Tanimoto Similarity between the Input Compound and Known Ligands of the Identified Target</b>:
this serves as an additional indicator of the confidence level in the predicted potential targets –
higher similarities usually correspond to greater prediction confidence.<br>
""")
                        target_identify_opts = gr.CheckboxGroup(
                            choices=TARGET_IDENTIFY_CPI_OPTS,
                            value=TARGET_IDENTIFY_CPI_OPTS[0],
                            label='Step 6. Select Advanced Options',
                            info="Advanced features - may increase the job computation time. "
                                 "See the Help Tip on the right or the Documentation for detailed explanation."
                        )
                with gr.Row():
                    with gr.Column():
                        target_identify_email = gr.Textbox(
                            label='Step 7. Input Your Email Address (Optional)',
                            info="Your email address will be used to notify you of the status of your job. "
                                 "If you cannot receive the email, please check your spam/junk folder."
                        )

                with gr.Row(visible=True):
                    target_identify_clr_btn = gr.ClearButton(size='lg')
                    target_identify_btn = gr.Button(value='SUBMIT THE IDENTIFICATION JOB', variant='primary',
                                                    size='lg')

            identify_data_for_predict = gr.File(visible=False, file_count="single", type='filepath')

        with gr.TabItem(label='Interaction Pair Inference', id='Interaction Pair Inference'):
            gr.Markdown('''
            # <center>Interaction Pair Inference</center>
            
            <center>To predict interactions or binding affinities between up to 
            10,000 paired compound-protein data.</center>
            ''')
            HelpTip(
                "A custom interation pair dataset can be a CSV file with 2 required columns "
                "(X1 for smiles and X2 for sequences) "
                "and optionally 2 ID columns (ID1 for compound ID and ID2 for target ID), "
                "or generated from a FASTA file containing multiple "
                "sequences and a SDF file containing multiple compounds. "
                "Currently, a maximum of 10,000 pairs is supported, "
                "which means that the size of CSV file or "
                "the product of the two library sizes should not exceed 10,000."
            )
            infer_type = gr.Dropdown(
                choices=['Upload a CSV file containing paired compound-protein data',
                         'Upload a compound library and a target library'],
                label='Step 1. Select Pair Input Type and Input',
                value='Upload a CSV file containing paired compound-protein data')
            with gr.Column() as pair_upload:
                gr.File(
                    label="Example CSV dataset",
                    value="data/examples/interaction_pair_inference.csv",
                    interactive=False
                )
                with gr.Row():
                    infer_csv_prompt = gr.Button(
                        value="Upload Your Own Dataset Below",
                        variant='secondary')
                with gr.Column():
                    infer_pair = gr.File(
                        label='Upload CSV File Containing Paired Records',
                        file_count="single",
                        type='filepath',
                        visible=True
                    )
            with gr.Column(visible=False) as pair_generate:
                with gr.Row():
                    gr.File(
                        label='Example SDF compound library',
                        value='data/examples/compound_library.sdf',
                        interactive=False
                    )
                    gr.File(
                        label='Example FASTA target library',
                        value='data/examples/target_library.fasta',
                        interactive=False
                    )
                with gr.Row():
                    gr.File(
                        label='Example CSV compound library',
                        value='data/examples/compound_library.csv',
                        interactive=False
                    )
                    gr.File(
                        label='Example CSV target library',
                        value='data/examples/target_library.csv',
                        interactive=False
                    )
                with gr.Row():
                    infer_library_prompt = gr.Button(
                        value="Upload Your Own Libraries Below",
                        visible=False,
                        variant='secondary'
                    )
                with gr.Row():
                    infer_drug = gr.File(
                        label='Upload SDF/CSV File Containing Multiple Compounds',
                        file_count="single",
                        type='filepath'
                    )
                    infer_target = gr.File(
                        label='Upload FASTA/CSV File Containing Multiple Targets',
                        file_count="single",
                        type='filepath'
                    )

            with gr.Row():
                with gr.Column(min_width=200):
                    HelpTip(
                        "By default, models trained on all protein families (general) will be applied. "
                        "If the proteins in the target library of interest "
                        "all belong to the same protein family, manually selecting the family is supported."
                    )

                    pair_infer_target_family = gr.Dropdown(
                        choices=list(TARGET_FAMILY_MAP.keys()),
                        value='General',
                        label='Step 2. Select Target Family (Optional)'
                    )

                with gr.Column(min_width=200):
                    HelpTip(
                        "Interaction prediction provides you binding probability score "
                        "between the target of interest and each compound in the library, "
                        "while affinity prediction directly estimates their binding strength "
                        "measured using half maximal inhibitory concentration (IC<sub>50</sub>) in units of nM."
                    )
                    pair_infer_task = gr.Dropdown(
                        list(TASK_MAP.keys()),
                        label='Step 3. Select a Prediction Task',
                        value='Compound-Protein Interaction'
                    )

                with gr.Column(min_width=200):
                    HelpTip(
                        "Select your preferred model. Please refer to documentation for detailed benchmark results."
                    )
                    pair_infer_preset = gr.Dropdown(
                        list(PRESET_MAP.keys()),
                        label='Step 4. Select a Preset Model'
                    )
                    # infer_preset_recommend_btn = gr.Button(value='OR Let Us Recommend for You',
                    #                                        variant='primary')
            pair_infer_opts = gr.CheckboxGroup(visible=False)

            with gr.Row():
                pair_infer_email = gr.Textbox(
                    label='Step 5. Input Your Email Address (Optional)',
                    info="Your email address will be used to notify you of the status of your job. "
                         "If you cannot receive the email, please check your spam/junk folder.")

            with gr.Row(visible=True):
                pair_infer_clr_btn = gr.ClearButton(size='lg')
                pair_infer_btn = gr.Button(value='SUBMIT THE INFERENCE JOB', variant='primary', size='lg')

            infer_data_for_predict = gr.File(file_count="single", type='filepath', visible=False)

        with gr.TabItem(label='Chemical Property Report', id='Chemical Property Report'):
            gr.Markdown('''
            # <center>Chemical Property Report</center>
      
            To compute chemical properties for the predictions of Drug Hit Screening, 
            Target Protein Identification, and Interaction Pair Inference. 
            
            You may also upload your own dataset using a CSV file containing 
            one required column `X1` for compound SMILES. 
            
            The page shows only a preview report displaying at most 30 records 
            (with top predicted CPI/CPA if reporting results from a prediction job). 
            
            Please first `Preview` the report, then `Generate` and download a CSV report 
            or an interactive HTML report below if you wish to access the full report.
            ''')
            raw_df = gr.State(value=pd.DataFrame())
            report_df = gr.State(value=pd.DataFrame())
            with gr.Row():
                with gr.Column(scale=1):
                    file_for_report = gr.File(interactive=True, type='filepath')
                    report_task = gr.Dropdown(list(TASK_MAP.keys()), visible=False,
                                              value='Compound-Protein Interaction',
                                              label='Specify the Task Labels in the Uploaded Dataset')
                with gr.Column(scale=2):
                    with gr.Column():
                        with gr.Row():
                            scores = gr.CheckboxGroup(list(SCORE_MAP.keys()), label='Compound Scores')
                            filters = gr.CheckboxGroup(list(FILTER_MAP.keys()), label='Compound Filters')
                        job_opts = gr.CheckboxGroup(visible=False)

                    with gr.Accordion('Report Generate Options', open=True):
                        with gr.Row():
                            csv_sep = gr.Radio(label='CSV Delimiter',
                                               choices=['Comma', 'Tab'], value='Comma')
                            html_opts = gr.CheckboxGroup(label='HTML Report Options',
                                                         choices=[
                                                             'Exclude Molecular Graph',
                                                             'Exclude Scaffold Graph',
                                                             'Exclude Pharmacophore 3D'
                                                         ])

            with gr.Row():
                report_clr_btn = gr.ClearButton(size='lg')
                analyze_btn = gr.Button('Calculate Properties and Preview', variant='primary',
                                        size='lg', interactive=False)

            with gr.Row():
                with gr.Column(scale=3):
                    html_report = gr.HTML()  # label='Results', visible=True)
                    ranking_pie_chart = gr.Plot(visible=False)

            with gr.Row():
                with gr.Column():
                    csv_generate = gr.Button(value='Generate CSV Report',
                                             interactive=False, variant='primary')
                    csv_download_file = gr.File(label='Download CSV Report', visible=False)
                with gr.Column():
                    html_generate = gr.Button(value='Generate HTML Report',
                                              interactive=False, variant='primary')
                    html_download_file = gr.File(label='Download HTML Report', visible=False)

        with gr.TabItem(label='Prediction Status Lookup', id='Prediction Status Lookup'):
            gr.Markdown('''
            # <center>Prediction Status Lookup</center>
            
            To check the status of an in-progress or historical job using the job ID and retrieve the predictions 
            if the job has completed. Note that predictions are only kept for 48 hours upon job completion.
            
            You will be redirected to Chemical Property Report for carrying out further analysis and 
            generating the full report when the job is done. If the Lookup fails to respond, please wait for a 
            few minutes and refresh the page to try again. 
            ''')
            with gr.Column():
                pred_lookup_id = gr.Textbox(
                    label='Input Your Job ID', placeholder='e.g., e9dfd149-3f5c-48a6-b797-c27d027611ac',
                    info="Your job ID is a UUID4 string that you receive after submitting a job on the "
                         "page or in the email notification.")
                pred_lookup_btn = gr.Button(value='Lookup the Job Status', variant='primary', visible=True)
                pred_lookup_stop_btn = gr.Button(value='Stop Tracking', variant='stop', visible=False)
                pred_lookup_status = gr.Markdown()

                # retrieve_email = gr.Textbox(label='Step 2. Input Your Email Address', placeholder='e.g.,


    def target_input_type_select(input_type):
        match input_type:
            case 'UniProt ID':
                return [gr.Dropdown(info=''),
                        gr.UploadButton(visible=False),
                        gr.Textbox(visible=True, value=''),
                        gr.Textbox(visible=False, value=''),
                        gr.Textbox(visible=False, value=''),
                        gr.Button(visible=True),
                        gr.Code(value=''),
                        gr.Button(visible=False)]
            case 'Gene symbol':
                return [gr.Dropdown(info=''),
                        gr.UploadButton(visible=False),
                        gr.Textbox(visible=False, value=''),
                        gr.Textbox(visible=True, value=''),
                        gr.Textbox(visible=True, value=''),
                        gr.Button(visible=True),
                        gr.Code(value=''),
                        gr.Button(visible=False)]
            case 'Sequence':
                return [gr.Dropdown(info='Enter (paste) a FASTA string below manually or upload a FASTA file.'),
                        gr.UploadButton(visible=True),
                        gr.Textbox(visible=False, value=''),
                        gr.Textbox(visible=False, value=''),
                        gr.Textbox(visible=False, value=''),
                        gr.Button(visible=False),
                        gr.Code(value=''),
                        gr.Button(visible=True)]


    target_input_type.select(
        fn=target_input_type_select,
        inputs=target_input_type,
        outputs=[
            target_input_type, target_upload_btn,
            target_id, target_gene, target_organism, target_query_btn,
            target_fasta, target_paste_markdown
        ],
        show_progress='hidden'
    )


    def uniprot_query(input_type, uid, gene, organism='Human'):
        uniprot_endpoint = 'https://rest.uniprot.org/uniprotkb/{query}'
        fasta_rec = ''

        match input_type:
            case 'UniProt ID':
                query = f"{uid.strip()}.fasta"
            case 'Gene symbol':
                organism = organism if organism else 'Human'
                query = f'search?query=organism_name:{organism.strip()}+AND+gene:{gene.strip()}&format=fasta'

        try:
            fasta = session.get(uniprot_endpoint.format(query=query))
            fasta.raise_for_status()
            if fasta.text:
                fasta_rec = next(SeqIO.parse(io.StringIO(fasta.text), format='fasta'))
                fasta_rec = f">{fasta_rec.description}\n{fasta_rec.seq}"

        except Exception as e:
            raise gr.Warning(f"Failed to query FASTA from UniProt database due to {str(e)}")
        finally:
            return fasta_rec


    def process_fasta_upload(fasta_upload):
        fasta = ''
        try:
            fasta = fasta_upload.decode()
        except Exception as e:
            gr.Warning(f"Please upload a valid FASTA file. Error: {str(e)}")
        return fasta


    target_upload_btn.upload(
        fn=process_fasta_upload, inputs=target_upload_btn, outputs=target_fasta
    ).then(
        fn=wrap_text, inputs=target_fasta, outputs=target_fasta, show_progress='hidden'
    )
    target_query_btn.click(
        fn=uniprot_query, inputs=[target_input_type, target_id, target_gene, target_organism], outputs=target_fasta
    ).then(
        fn=wrap_text, inputs=target_fasta, outputs=target_fasta, show_progress='hidden'
    )


    def target_family_detect(fasta, progress=gr.Progress(track_tqdm=True)):
        try:
            aligner = PairwiseAligner(mode='local')
            alignment_df = get_fasta_family_map()

            processed_fasta = process_target_fasta(fasta)

            # Check for an exact match first
            exact_match = alignment_df[alignment_df['X2'] == processed_fasta]
            if not exact_match.empty:
                row = exact_match.iloc[0]
                family = str(row['Target Family']).title()
                return gr.Dropdown(
                    value=family,
                    info=f"Reason: Exact match found with {row['ID2']} from family {family}")

            # If no exact match, then calculate alignment score
            def align_score(query):
                alignment = aligner.align(processed_fasta, query)
                return alignment.score / max(len(processed_fasta), len(query))

            alignment_df['score'] = alignment_df['X2'].parallel_apply(align_score)
            row = alignment_df.loc[alignment_df['score'].idxmax()]
            family = str(row['Target Family']).title()
            return gr.Dropdown(value=family,
                               info=f"Reason: Best sequence identity ({row['score']}) "
                                    f"with {row['ID2']} from family {family}")
        except Exception as e:
            gr.Warning("Failed to detect the protein family due to error: " + str(e))


    target_family_detect_btn.click(fn=target_family_detect, inputs=target_fasta, outputs=drug_screen_target_family)

    # target_fasta.focus(fn=wrap_text, inputs=target_fasta, outputs=target_fasta, show_progress='hidden')
    target_fasta.blur(fn=wrap_text, inputs=target_fasta, outputs=target_fasta, show_progress='hidden')

    drug_library_upload_btn.upload(fn=lambda x: [
        x.name, gr.Dropdown(value=Path(x.name).name, choices=list(DRUG_LIBRARY_MAP.keys()) + [Path(x.name).name])
    ], inputs=drug_library_upload_btn, outputs=[drug_library_upload, drug_library])

    drug_screen_task.select(
        fn=lambda task, opts: gr.CheckboxGroup(choices=DRUG_SCRENN_CPA_OPTS)
        if task == 'Compound-Protein Binding Affinity' else gr.CheckboxGroup(
            choices=DRUG_SCRENN_CPI_OPTS, value=DRUG_SCRENN_CPI_OPTS[0]),
        inputs=[drug_screen_task, drug_screen_opts], outputs=drug_screen_opts,
        show_progress='hidden'
    )

    target_identify_task.select(
        fn=lambda task, opts: gr.CheckboxGroup(choices=TARGET_IDENTIFY_CPA_OPTS)
        if task == 'Compound-Protein Binding Affinity' else gr.CheckboxGroup(
            choices=TARGET_IDENTIFY_CPI_OPTS, value=TARGET_IDENTIFY_CPI_OPTS[0]),
        inputs=[target_identify_task, target_identify_opts], outputs=target_identify_opts,
        show_progress='hidden'
    )

    def example_fill(input_type):
        return {target_id: 'Q16539',
                target_gene: 'MAPK14',
                target_organism: 'Human',
                target_fasta: """
>sp|Q16539|MK14_HUMAN Mitogen-activated protein kinase 14 OS=Homo sapiens OX=9606 GN=MAPK14 PE=1 SV=3
MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQ
SIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQ
KLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMT
GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVG
TPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAA
QALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
"""}


    example_fasta.click(fn=example_fill, inputs=target_input_type, outputs=[
        target_id, target_gene, target_organism, target_fasta], show_progress='hidden')


    def screen_recommend_model(fasta, family, task):
        task = TASK_MAP[task]
        score = TASK_METRIC_MAP[task]
        benchmark_df = pd.read_csv(f'data/benchmarks/{task}_test_metrics.csv')

        if not fasta:
            gr.Warning('Please enter a valid FASTA for model recommendation.')
            return [None, family]

        if family == 'General':
            seen_targets = get_seen_fastas('General', task)['X2'].values
            if process_target_fasta(fasta) in seen_targets:
                scenario = "Seen Target"
            else:
                scenario = "Unseen Target"
            filtered_df = benchmark_df[(benchmark_df['Family'] == 'All Families')
                                       & (benchmark_df['Scenario'] == scenario)
                                       & (benchmark_df['Type'] == 'General')]

        else:
            seen_targets_general = get_seen_fastas('General', task)['X2'].values
            if process_target_fasta(fasta) in seen_targets_general:
                scenario_general = "Seen Target"
            else:
                scenario_general = "Unseen Target"

            seen_targets_family = get_seen_fastas(family, task)['X2'].values
            if process_target_fasta(fasta) in seen_targets_family:
                scenario_family = "Seen Target"
            else:
                scenario_family = "Unseen Target"

            filtered_df_general = benchmark_df[(benchmark_df['Family'] == family)
                                               & (benchmark_df['Scenario'] == scenario_general)
                                               & (benchmark_df['Type'] == 'General')]
            filtered_df_family = benchmark_df[(benchmark_df['Family'] == family)
                                              & (benchmark_df['Scenario'] == scenario_family)
                                              & (benchmark_df['Type'] == 'Family')]
            filtered_df = pd.concat([filtered_df_general, filtered_df_family])

        row = filtered_df.loc[filtered_df[score].idxmax()]
        if row['Scenario'] == 'Seen Target':
            scenario = "Seen Target (>=0.85 sequence identity)"
        elif row['Scenario'] == 'Unseen Target':
            scenario = "Unseen Target (<0.85 sequence identity)"

        return {drug_screen_preset:
                    gr.Dropdown(value=row['Model'],
                                info=f"Reason: {row['Scenario']} in training; we recommend the {row['Type']}-trained "
                                     f"model with the best {score} in the {scenario} scenario on {row['Family']}."),
                drug_screen_target_family:
                    gr.Dropdown(value='General') if row['Type'] == 'General' else gr.Dropdown(value=family)}


    screen_preset_recommend_btn.click(
        fn=screen_recommend_model,
        inputs=[target_fasta, drug_screen_target_family, drug_screen_task],
        outputs=[drug_screen_preset, drug_screen_target_family],
        show_progress='hidden'
    )


    def compound_input_type_select(input_type):
        match input_type:
            case 'SMILES':
                return gr.Button(visible=False)
            case 'SDF':
                return gr.Button(visible=True)


    compound_type.select(fn=compound_input_type_select,
                         inputs=compound_type, outputs=compound_upload_btn, show_progress='hidden')


    def compound_upload_process(input_type, input_upload):
        smiles = ''
        try:
            match input_type:
                case 'SMILES':
                    smiles = input_upload.decode()
                case 'SDF':
                    suppl = Chem.ForwardSDMolSupplier(io.BytesIO(input_upload))
                    smiles = Chem.MolToSmiles(next(suppl))
        except Exception as e:
            gr.Warning(f"Please upload a valid {input_type} file. Error: {str(e)}")
        return smiles


    compound_upload_btn.upload(fn=compound_upload_process,
                               inputs=[compound_type, compound_upload_btn],
                               outputs=compound_smiles)

    example_drug.click(fn=lambda: 'CC(=O)Oc1ccccc1C(=O)O', outputs=compound_smiles, show_progress='hidden')

    target_library_upload_btn.upload(fn=lambda x: [
        x.name, gr.Dropdown(value=Path(x.name).name, choices=list(TARGET_LIBRARY_MAP.keys()) + [Path(x.name).name])
    ], inputs=target_library_upload_btn, outputs=[target_library_upload, target_library])


    def identify_recommend_model(smiles, family, task):
        task = TASK_MAP[task]
        score = TASK_METRIC_MAP[task]
        benchmark_df = pd.read_csv(f'data/benchmarks/{task}_test_metrics.csv')

        if not smiles:
            gr.Warning('Please enter a valid SMILES for model recommendation.')
            return None
        if family == 'Family-Specific Auto-Recommendation':
            return 'Family-Specific Auto-Recommendation'

        if family == 'General':
            seen_compounds = pd.read_csv(
                f'data/benchmarks/seen_compounds/all_families_full_{task.lower()}_random_split.csv')
            family = 'All Families'

        else:
            seen_compounds = pd.read_csv(
                f'data/benchmarks/seen_compounds/{TARGET_FAMILY_MAP[family.title()]}_{task.lower()}_random_split.csv')

        if rdkit_canonicalize(smiles) in seen_compounds['X1'].values:
            scenario = "Seen Compound"
        else:
            scenario = "Unseen Compound"

        filtered_df = benchmark_df[(benchmark_df['Family'] == family)
                                   & (benchmark_df['Scenario'] == scenario)
                                   & (benchmark_df['Type'] == 'General')]

        row = filtered_df.loc[filtered_df[score].idxmax()]

        return gr.Dropdown(value=row['Model'],
                           info=f"Reason: {scenario} in training; choosing the model "
                                f"with the best {score} in the {scenario} scenario.")


    identify_preset_recommend_btn.click(fn=identify_recommend_model,
                                        inputs=[compound_smiles, target_identify_target_family, target_identify_task],
                                        outputs=target_identify_preset, show_progress='hidden')


    def infer_type_change(upload_type):
        match upload_type:
            case "Upload a compound library and a target library":
                return {
                    pair_upload: gr.Column(visible=False),
                    pair_generate: gr.Column(visible=True),
                    infer_pair: None,
                    infer_drug: None,
                    infer_target: None,
                    infer_csv_prompt: gr.Button(visible=False),
                    infer_library_prompt: gr.Button(visible=True),
                }
            case "Upload a CSV file containing paired compound-protein data":
                return {
                    pair_upload: gr.Column(visible=True),
                    pair_generate: gr.Column(visible=False),
                    infer_pair: None,
                    infer_drug: None,
                    infer_target: None,
                    infer_csv_prompt: gr.Button(visible=True),
                    infer_library_prompt: gr.Button(visible=False),
                }


    infer_type.select(fn=infer_type_change, inputs=infer_type,
                      outputs=[pair_upload, pair_generate, infer_pair, infer_drug, infer_target,
                               infer_csv_prompt, infer_library_prompt],
                      show_progress='hidden')


    def common_input_validate(state, preset, email, request):
        gr.Info('Start processing inputs...')
        if not preset:
            raise gr.Error('Please select a model.')

        if email:
            try:
                email_info = validate_email(email, check_deliverability=False)
                email = email_info.normalized
            except EmailNotValidError as e:
                raise gr.Error(f"Invalid email address: {str(e)}.")

        if state:
            raise gr.Error(f"You already have a running prediction job (ID: {state['id']}) under this session. "
                           "Please wait for it to complete before submitting another job.")

        if check := check_user_running_job(email, request):
            raise gr.Error(check)

        return state, preset, email


    def common_job_initiate(job_id, job_type, email, request, task):
        gr.Info('Finished processing inputs. Initiating the prediction job... '
                'You will be redirected to Prediction Status Lookup once the job has been submitted.')
        job_info = {'id': job_id,
                    'type': job_type,
                    'task': task,
                    'status': 'RUNNING',
                    'email': email,
                    'ip': request.headers.get('x-forwarded-for', request.client.host),
                    'cookies': dict(request.cookies),
                    'start_time': time(),
                    'end_time': None,
                    'expiry_time': None,
                    'error': None}
        # db.insert(job_info)
        return job_info


    def drug_screen_validate(fasta, library, library_upload, preset, task, email, state,
                             request: gr.Request, progress=gr.Progress(track_tqdm=True)):
        state, preset, email = common_input_validate(state, preset, email, request)

        fasta = process_target_fasta(fasta)
        err = validate_seq_str(fasta, FASTA_PAT)
        if err:
            raise gr.Error(f'Found error(s) in your Target FASTA input: {err}')
        if not library:
            raise gr.Error('Please select or upload a compound library.')
        if library in DRUG_LIBRARY_MAP.keys():
            screen_df = pd.read_csv(Path('data/drug_libraries', DRUG_LIBRARY_MAP[library]))
        else:
            screen_df = process_drug_library_upload(library_upload)
            if len(screen_df) >= DATASET_MAX_LEN:
                raise gr.Error(f'The uploaded compound library has more records '
                               f'than the allowed maximum {DATASET_MAX_LEN}.')

        screen_df['X2'] = fasta

        job_id = str(uuid4())
        temp_file = Path(f'{SERVER_DATA_DIR}/{job_id}_input.csv').resolve()
        screen_df.to_csv(temp_file, index=False, na_rep='')
        if temp_file.is_file():
            job_info = common_job_initiate(job_id, 'Drug Hit Screening', email, request, task)
            return {screen_data_for_predict: str(temp_file),
                    run_state: job_info}
        else:
            raise gr.Error('System failed to create temporary files. Please try again later.')


    def target_identify_validate(smiles, library, library_upload, preset, task, email, state,
                                 request: gr.Request, progress=gr.Progress(track_tqdm=True)):
        state, preset, email = common_input_validate(state, preset, email, request)

        smiles = smiles.strip()
        err = validate_seq_str(smiles, SMILES_PAT)
        if err:
            raise gr.Error(f'Found error(s) in your Compound SMILES input: {err}')
        if not library:
            raise gr.Error('Please select or upload a target library.')
        if library in TARGET_LIBRARY_MAP.keys():
            identify_df = pd.read_csv(Path('data/target_libraries', TARGET_LIBRARY_MAP[library]))
        else:
            identify_df = process_target_library_upload(library_upload)
            if len(identify_df) >= DATASET_MAX_LEN:
                raise gr.Error(f'The uploaded target library has more records '
                               f'than the allowed maximum {DATASET_MAX_LEN}.')
        identify_df['X1'] = smiles

        job_id = str(uuid4())
        temp_file = Path(f'{SERVER_DATA_DIR}/{job_id}_input.csv').resolve()
        identify_df.to_csv(temp_file, index=False, na_rep='')
        if temp_file.is_file():
            job_info = common_job_initiate(job_id, 'Target Protein Identification', email, request, task)
            return {identify_data_for_predict: str(temp_file),
                    run_state: job_info}
        else:
            raise gr.Error('System failed to create temporary files. Please try again later.')


    def pair_infer_validate(drug_target_pair_upload, drug_upload, target_upload, preset, task, email, state,
                            request: gr.Request, progress=gr.Progress(track_tqdm=True)):
        state, preset, email = common_input_validate(state, preset, email, request)

        job_id = str(uuid4())
        if drug_target_pair_upload:
            infer_df = pd.read_csv(drug_target_pair_upload)
            validate_columns(infer_df, ['X1', 'X2'])

            infer_df['X1_ERR'] = infer_df['X1'].parallel_apply(
                validate_seq_str, regex=SMILES_PAT)
            if not infer_df['X1_ERR'].isna().all():
                raise ValueError(
                    f"Encountered invalid SMILES:\n{infer_df[~infer_df['X1_ERR'].isna()][['X1', 'X1_ERR']]}")

            infer_df['X2_ERR'] = infer_df['X2'].parallel_apply(
                validate_seq_str, regex=FASTA_PAT)
            if not infer_df['X2_ERR'].isna().all():
                raise ValueError(
                    f"Encountered invalid FASTA:\n{infer_df[~infer_df['X2_ERR'].isna()][['X2', 'X2_ERR']]}")

            temp_file = Path(drug_target_pair_upload).resolve()

        elif drug_upload and target_upload:
            drug_df = process_drug_library_upload(drug_upload)
            target_df = process_target_library_upload(target_upload)

            drug_df.drop_duplicates(subset=['X1'], inplace=True)
            target_df.drop_duplicates(subset=['X2'], inplace=True)

            infer_df = pd.DataFrame(list(itertools.product(drug_df['X1'], target_df['X2'])),
                                    columns=['X1', 'X2'])
            infer_df = infer_df.merge(drug_df, on='X1').merge(target_df, on='X2')

            if len(infer_df) >= DATASET_MAX_LEN:
                raise gr.Error(f'The uploaded/generated compound-protein pair dataset has more records '
                               f'than the allowed maximum {DATASET_MAX_LEN}.')

            temp_file = Path(f'{SERVER_DATA_DIR}/{job_id}_input.csv').resolve()
            infer_df.to_csv(temp_file, index=False, na_rep='')

        else:
            raise gr.Error('Should upload a compound-protein pair dataset, or '
                           'upload both a compound library and a target library.')

        if temp_file.is_file():
            job_info = common_job_initiate(job_id, 'Interaction Pair Inference', email, request, task)
            return {infer_data_for_predict: str(temp_file),
                    run_state: job_info}
        else:
            raise gr.Error('System failed to create temporary files. Please try again later.')


    def fill_job_id(job_info):
        try:
            return job_info['id']
        except Exception as e:
            gr.Warning(f'Failed to fetch job ID due to error: {str(e)}')
            return ''


    drug_screen_click = drug_screen_btn.click(
        fn=drug_screen_validate,
        inputs=[target_fasta, drug_library, drug_library_upload, drug_screen_preset, drug_screen_task,
                drug_screen_email, run_state],
        outputs=[screen_data_for_predict, run_state],
        concurrency_limit=2,
    )

    drug_screen_lookup = drug_screen_click.success(
        fn=lambda: gr.Tabs(selected='Prediction Status Lookup'), outputs=[tabs],
    ).then(
        fn=fill_job_id, inputs=[run_state], outputs=[pred_lookup_id]
    ).then(
        fn=lookup_job,
        inputs=[pred_lookup_id],
        outputs=[pred_lookup_status, pred_lookup_btn, pred_lookup_stop_btn, tabs, file_for_report],
        show_progress='minimal',
        concurrency_limit=100,
    )

    # drug_screen_click.success(
    #     fn=send_email,
    #     inputs=[run_state]
    # )

    drug_screen_click.success(
        fn=submit_predict,
        inputs=[screen_data_for_predict, drug_screen_task, drug_screen_preset,
                drug_screen_target_family, drug_screen_opts, run_state, ],
        outputs=[run_state, ]
    )

    drug_screen_clr_btn.click(
        lambda: ['General'] + [[]] + [None] * 5,
        outputs=[drug_screen_target_family, drug_screen_opts,
                 target_fasta, drug_screen_preset, drug_library, drug_library_upload, drug_screen_email],
        show_progress='hidden'
    )

    target_identify_clr_btn.click(
        lambda: ['General'] + [[]] + [None] * 5,
        outputs=[target_identify_target_family, target_identify_opts,
                 compound_smiles, target_identify_preset, target_library, target_library_upload, target_identify_email],
        show_progress='hidden'
    )

    pair_infer_clr_btn.click(
        lambda: ['General'] + [None] * 5,
        outputs=[pair_infer_target_family,
                 infer_pair, infer_drug, infer_target, pair_infer_preset, pair_infer_email],
        show_progress='hidden'
    )

    report_clr_btn.click(
        lambda: [[]] * 3 + [None] * 3 +
                [gr.Button(interactive=False)] * 3 +
                [gr.File(visible=False, value=None)] * 2 +
                [gr.Dropdown(visible=False, value=None), gr.HTML(value=''), gr.CheckboxGroup(visible=False)],
        outputs=[
            scores, filters, html_opts,
            file_for_report, raw_df, report_df,
            csv_generate, html_generate, analyze_btn,
            csv_download_file, html_download_file,
            report_task, html_report, job_opts
        ],
        show_progress='hidden'
    )


    def update_preset(family, preset):
        if family == 'Family-Specific Auto-Recommendation':
            return 'Family-Specific Auto-Recommendation'
        elif preset == 'Family-Specific Auto-Recommendation':
            return None
        else:
            return preset


    def update_family(family, preset):
        if preset == 'Family-Specific Auto-Recommendation':
            return 'Family-Specific Auto-Recommendation'
        elif family == 'Family-Specific Auto-Recommendation':
            return None
        else:
            return family


    target_identify_target_family.change(
        fn=update_preset, inputs=[target_identify_target_family, target_identify_preset],
        outputs=target_identify_preset, show_progress='hidden')
    target_identify_preset.change(
        fn=update_family, inputs=[target_identify_target_family, target_identify_preset],
        outputs=target_identify_target_family, show_progress='hidden')

    target_identify_click = target_identify_btn.click(
        fn=target_identify_validate,
        inputs=[compound_smiles, target_library, target_library_upload, target_identify_preset, target_identify_task,
                target_identify_email, run_state],
        outputs=[identify_data_for_predict, run_state],
        concurrency_limit=2,
    )

    target_identify_lookup = target_identify_click.success(
        fn=lambda: gr.Tabs(selected='Prediction Status Lookup'), outputs=[tabs],
    ).then(
        fn=fill_job_id, inputs=[run_state], outputs=[pred_lookup_id]
    ).then(
        fn=lookup_job,
        inputs=[pred_lookup_id],
        outputs=[pred_lookup_status, pred_lookup_btn, pred_lookup_stop_btn, tabs, file_for_report],
        show_progress='minimal',
        concurrency_limit=100
    )

    # target_identify_click.success(
    #     fn=send_email,
    #     inputs=[run_state]
    # )

    target_identify_click.success(
        fn=submit_predict,
        inputs=[identify_data_for_predict, target_identify_task, target_identify_preset,
                target_identify_target_family, target_identify_opts, run_state, ],  # , target_identify_email],
        outputs=[run_state, ]
    )

    pair_infer_click = pair_infer_btn.click(
        fn=pair_infer_validate,
        inputs=[infer_pair, infer_drug, infer_target, pair_infer_preset, pair_infer_task,
                pair_infer_email, run_state],
        outputs=[infer_data_for_predict, run_state],
        concurrency_limit=2,
    )

    pair_infer_lookup = pair_infer_click.success(
        fn=lambda: gr.Tabs(selected='Prediction Status Lookup'), outputs=[tabs],
    ).then(
        fn=fill_job_id, inputs=[run_state], outputs=[pred_lookup_id]
    ).then(
        fn=lookup_job,
        inputs=[pred_lookup_id],
        outputs=[pred_lookup_status, pred_lookup_btn, pred_lookup_stop_btn, tabs, file_for_report],
        show_progress='minimal',
        concurrency_limit=100
    )

    # pair_infer_click.success(
    #     fn=send_email,
    #     inputs=[run_state]
    # )

    pair_infer_click.success(
        fn=submit_predict,
        inputs=[infer_data_for_predict, pair_infer_task, pair_infer_preset,
                pair_infer_target_family, pair_infer_opts, run_state, ],  # , pair_infer_email],
        outputs=[run_state, ]
    )

    pred_lookup_click = pred_lookup_btn.click(
        fn=lookup_job,
        inputs=[pred_lookup_id],
        outputs=[pred_lookup_status, pred_lookup_btn, pred_lookup_stop_btn, tabs, file_for_report],
        show_progress='minimal',
        cancels=[drug_screen_lookup, target_identify_lookup, pair_infer_lookup],
        concurrency_limit=100,
    )

    pred_lookup_stop_btn.click(
        fn=lambda: [gr.Button(visible=True), gr.Button(visible=False)],
        outputs=[pred_lookup_btn, pred_lookup_stop_btn],
        cancels=[pred_lookup_click, drug_screen_lookup, target_identify_lookup, pair_infer_lookup],
        concurrency_limit=None,
    )


    def inquire_task(df):
        if 'Y^' in df.columns:
            label = 'predicted CPI/CPA labels (`Y^`)'
            return {report_task: gr.Dropdown(visible=True,
                                             info=f'Found {label} in your uploaded dataset. '
                                                  'Is it compound-protein interaction or binding affinity?'),
                    html_report: ''}
        else:
            return {report_task: gr.Dropdown(visible=False)}

    report_df_change = file_for_report.change(
        fn=update_df, inputs=file_for_report, outputs=[
            html_report, raw_df, report_df, analyze_btn, report_task, job_opts
        ],
        concurrency_limit=100,
    ).success(
        fn=lambda: [gr.Button(interactive=True)] * 3 +
                   [gr.File(visible=False, value=None)] * 2,
        outputs=[
            csv_generate, html_generate, analyze_btn, csv_download_file, html_download_file
        ],
    )

    file_for_report.upload(
        # fn=update_df, inputs=file_for_report, outputs=[
        #     html_report, raw_df, report_df, analyze_btn, report_task, job_opts
        # ],
        # cancels=[report_df_change],
        # concurrency_limit=100,
        # ).success(
        fn=inquire_task, inputs=[raw_df],
        outputs=[report_task, html_report],
    )

    file_for_report.clear(
        fn=lambda: [gr.Button(interactive=False)] * 3 +
                   [gr.File(visible=False, value=None)] * 2 +
                   [gr.Dropdown(visible=False, value=None), '', gr.CheckboxGroup(visible=False)],
        cancels=[report_df_change],
        outputs=[
            csv_generate, html_generate, analyze_btn,
            csv_download_file, html_download_file,
            report_task, html_report, job_opts
        ]
    )

    analyze_btn.click(
        fn=submit_report, inputs=[raw_df, scores, filters, job_opts, report_task], outputs=[
            html_report, report_df, csv_download_file, html_download_file]
    ).success(
        fn=lambda: [gr.Button(interactive=True)] * 2,
        outputs=[csv_generate, html_generate],
        concurrency_limit=100,
    )


    def create_csv_report_file(df, file_report, task, sep, progress=gr.Progress(track_tqdm=True)):
        csv_sep_map = {
            'Comma': ',',
            'Tab': '\t',
        }
        y_colname = 'Y^'
        if isinstance(task, str):
            if task == 'Compound-Protein Interaction':
                y_colname = 'Y_prob'
            elif task == 'Compound-Protein Binding Affinity':
                y_colname = 'Y_IC50'
        try:
            now = datetime.now().strftime("%Y-%m-%d_%H-%M-%S")
            filename = f"{SERVER_DATA_DIR}/{Path(file_report.name).stem}_DeepSEQreen_report_{now}.csv"
            df.rename(columns={'Y^': y_colname}).drop(
                labels=['Compound', 'Scaffold'], axis=1
            ).to_csv(filename, index=False, na_rep='', sep=csv_sep_map[sep])

            return gr.File(filename, visible=True)
        except Exception as e:
            gr.Warning(f"Failed to generate CSV due to error: {str(e)}")
            return None


    def create_html_report_file(df, file_report, task, opts, progress=gr.Progress(track_tqdm=True)):
        try:
            now = datetime.now().strftime("%Y-%m-%d_%H-%M-%S")
            filename = f"{SERVER_DATA_DIR}/{Path(file_report.name).stem}_DeepSEQreen_report_{now}.html"
            create_html_report(df, filename, task, opts)
            return gr.File(filename, visible=True)
        except Exception as e:
            gr.Warning(f"Failed to generate HTML due to error: {str(e)}")
            return None


    # html_report.change(lambda: [gr.Button(visible=True)] * 2, outputs=[csv_generate, html_generate])

    csv_generate.click(
        lambda: gr.File(visible=True), outputs=csv_download_file,
    ).then(
        fn=create_csv_report_file, inputs=[report_df, file_for_report, report_task, csv_sep],
        outputs=csv_download_file, show_progress='full'
    )
    html_generate.click(
        lambda: gr.File(visible=True), outputs=html_download_file,
    ).then(
        fn=create_html_report_file, inputs=[report_df, file_for_report, report_task, html_opts],
        outputs=html_download_file, show_progress='full'
    )

if __name__ == "__main__":
    pandarallel.initialize()

    hydra.initialize(version_base="1.3", config_path="configs", job_name="webserver_inference")

    session = requests.Session()
    ADAPTER = HTTPAdapter(max_retries=Retry(total=5, backoff_factor=0.1, status_forcelist=[500, 502, 503, 504]))
    session.mount('http://', ADAPTER)
    session.mount('https://', ADAPTER)

    db = TinyDB(f'{SERVER_DATA_DIR}/db.json')
    # Set all RUNNING jobs to FAILED at TinyDB initialization
    Job = Query()
    jobs = db.all()
    for job in jobs:
        if job['status'] == 'RUNNING':
            db.update({'status': 'FAILED'}, Job.id == job['id'])

    scheduler = BackgroundScheduler()
    scheduler.add_job(check_expiry, 'interval', hours=1, timezone=pytz.utc)
    scheduler.start()

    demo.queue(default_concurrency_limit=None, max_size=10).launch(show_api=False)