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This study presents a comprehensive computational investigation to evaluate the potential of a series of 1,2,4\u2010oxadiazole derivatives as dual inhibitors of the human epidermal growth factor receptor 2 (HER2) and estrogen receptor alpha (ER\u03b1), two key drivers in these malignancies. An integrated in silico strategy was employed, combining density functional theory (DFT), molecular docking and dynamics simulations, pharmacokinetic profiling, and machine learning models. Our workflow identified several lead compounds exhibiting promising dual\u2010binding characteristics. Key derivatives demonstrated superior predicted binding affinity and complex stability compared to the reference inhibitor erlotinib. Pharmacokinetic evaluations indicated that the series possesses favorable drug\u2010likeness, with high predicted oral bioavailability and a low risk of cardiotoxicity. Furthermore, machine and deep learning models achieved robust performance in classifying compound activity, underscoring their utility in virtual screening. Collectively, this work validates the 1,2,4\u2010oxadiazole core as a promising scaffold for dual HER2\/ER\u03b1 inhibition and provides a rational, multi\u2010faceted computational blueprint. The identified lead compounds warrant subsequent experimental validation, and the established framework serves as a valuable template for accelerating the discovery of next\u2010generation targeted cancer therapies.<\/jats:p>","DOI":"10.1002\/cbdv.202503520","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:41:21Z","timestamp":1774590081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual HER2\/ER\u03b1 Inhibitors for Breast and Ovarian Cancer: An Integrated Computational Study on 1,2,4\u2010Oxadiazole Derivatives"],"prefix":"10.1002","volume":"23","author":[{"given":"Muhammad Asim","family":"Khan","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Linyi University  Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Jabbar","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Linyi University  Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lala Rukh","family":"Sidra","sequence":"additional","affiliation":[{"name":"Department of Chemistry The Superior University  Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fakiha","family":"Naseem","sequence":"additional","affiliation":[{"name":"Department of Chemistry The Superior University  Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushey Asim","family":"Khan","sequence":"additional","affiliation":[{"name":"Cambridge International Education Pakistan Embassy College Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadaf","family":"Mutahir","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Linyi University  Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameerah I.","family":"Al\u2010Saeedi","sequence":"additional","affiliation":[{"name":"Department of Chemistry College of Science Princess Nourah bint Abdulrahman University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Chemistry College of Science Taif University  Taif Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangli","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Linyi University  Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"1429","volume-title":"The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling of the Present Scenario, Bioprospecting of Tropical Medicinal Plants","author":"Ghufran M. 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