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A library of 5000 compounds from the PubChem database was screened, and CID\u20102135609 emerged as the top hit with the strongest binding affinity (\u201312.39\u2009kcal\/mol). In addition to its superior docking score, CID\u20102135609 exhibited favorable drug\u2010like properties, including optimal molecular weight, high Caco\u20102 permeability, balanced lipophilicity, and acceptable blood\u2010brain barrier penetration. Molecular docking revealed that CID\u20102135609 engages key catalytic residues (Asp25, Ile50, Gly49) through van der Waals and \u03c0\u2010interactions, with additional contributions from Arg8, Asp30, and Ile47. Thermodynamic profiling indicated that binding is exothermic and entropically favorable, driven by hydrophobic contacts and water displacement, with a negative \u0394G confirming spontaneous association. All\u2010atom molecular dynamics simulations over 200\u2009ns demonstrated that CID\u20102135609 maintains stable binding within the active site, preserving critical contacts while adapting its orientation to enhance fit. The protease structure remained conformationally stable, with minimal deviation in secondary structure or global compactness. Time\u2010resolved interaction profiling revealed sustained and expanded interactions with residues including Pro81, Ile84, and Thr80. Comparative analysis with the apo form showed reduced solvent exposure and conformational flexibility upon ligand binding, as supported by SASA and PCA analyses. Free energy decomposition further validated complex stability. Overall, CID\u20102135609 is a promising candidate for HIV\u20101 protease inhibition and merits further experimental validation.<\/jats:p>","DOI":"10.1002\/jcb.70058","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T10:11:04Z","timestamp":1754993464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structure\u2010Based Identification and Molecular Characterization of CID\u20102135609 as a Potent Small Molecule Modulator of HIV\u20101 Protease"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5238","authenticated-orcid":false,"given":"S","family":"Rehan Ahmad","sequence":"first","affiliation":[{"name":"Hiralal Mazumdar Memorial College for Women West Bengal State University Kolkata West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.","family":"Zeyaullah","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus King Khalid University Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-1913","authenticated-orcid":false,"given":"Abdullah M.","family":"AlShahrani","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus King Khalid University Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3038-3105","authenticated-orcid":false,"given":"Ali","family":"Mohieldin","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences, Khamis Mushait Campus King Khalid University Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Shane","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, College of Applied Medical Sciences Jazan University Jazan Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-2607","authenticated-orcid":false,"given":"Abdelrhman A. 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