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This study employed an integrated computational approach combining Density Functional Theory (DFT), molecular docking, molecular dynamics (MD) simulations, and MM-PBSA calculations to evaluate 2-thiohydantoin derivatives as CDK2 inhibitors. DFT calculations revealed compounds\n                    <jats:bold>2b-e<\/jats:bold>\n                    narrowest lowest unoccupied molecular orbital (LUMO)- highest occupied molecular orbital (HOMO) gaps (3.02\u20133.26\u00a0eV in DMSO) and highest electrophilicity indices (&gt;\u20093.20\u00a0eV), indicating enhanced reactivity toward biological targets. QTAIM and Fukui function analyses identified key electrophilic centers (C2, O12, C14) and hydrogen bonding sites essential for protein interactions. Molecular docking against CDK2 (PDB: 1HCK) showed compounds\n                    <jats:bold>2c<\/jats:bold>\n                    ,\n                    <jats:bold>2d<\/jats:bold>\n                    , and\n                    <jats:bold>2b<\/jats:bold>\n                    exhibited superior binding affinities (-9.312, -9.303, and \u2212\u20099.269\u00a0kcal\/mol) compared to ATP (-8.460\u00a0kcal\/mol), forming critical hydrogen bonds with Lys33 and Thr14. The 10 ns MD simulations confirmed stable binding, with compound\n                    <jats:bold>2f<\/jats:bold>\n                    maintaining highest conformational stability (RMSD\u2009~\u20090.05\u00a0nm) and robust hydrogen bonding (mean: 2.70 bonds). MM-PBSA analysis revealed compound\n                    <jats:bold>2d<\/jats:bold>\n                    achieved optimal binding affinity (\u0394G_bind = -34.50\u2009\u00b1\u20090.42\u00a0kcal\/mol) through balanced van der Waals interactions (-50.74\u00a0kcal\/mol) and minimal desolvation penalty (52.40\u00a0kcal\/mol). Compounds\n                    <jats:bold>2b<\/jats:bold>\n                    ,\n                    <jats:bold>2c<\/jats:bold>\n                    ,\n                    <jats:bold>2d<\/jats:bold>\n                    , and\n                    <jats:bold>2f<\/jats:bold>\n                    emerged as lead candidates for experimental validation as next-generation CDK2-targeted anticancer agents.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-42330-4","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T08:27:44Z","timestamp":1774513664000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Integrated DFT, molecular docking, and molecular dynamics investigation of some novel 2-thiohydantoin analogues as potent CDK2 inhibitors for anticancer therapy"],"prefix":"10.1038","volume":"16","author":[{"given":"Nada A.","family":"Khaled","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayed A.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhat A.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama M.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neama A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagy M.","family":"Khalifa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"42330_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-024-00239-2","volume":"6","author":"Y Gu","year":"2025","unstructured":"Gu, Y. et al. 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