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An integrated computational approach, including molecular docking, pharmacophore modeling, molecular dynamics simulations, and DFT analysis, was employed to evaluate the binding affinity, stability, and pharmacological properties of FDA\u2010approved and experimental compounds. Structural validation of MEK1 (PDB ID: 1S9J) and MEK2 (PDB ID: 1S9I) revealed <jats:italic>z<\/jats:italic>\u2010scores of \u22126.89 and \u22127.13, respectively, with 90.6% and 86.7% of residues in the most favored regions, confirming the reliability of the protein models. Docking studies identified RO5126766 as a lead compound, exhibiting binding energies of \u221210.1\u00a0kcal\/mol with MEK1 and \u22129.5\u00a0kcal\/mol with MEK2. Molecular dynamics simulations further demonstrated the stability of the RO5126766\u2013MEK1 and RO5126766\u2013MEK2 complexes, with RMSD values ranging from 0.95 to 4.22\u00a0\u00c5. The in vitro anticancer assays highlighted the exceptional potency of RO5126766, with IC<jats:sub>50<\/jats:sub> values of 12.87\u00a0\u00b1\u00a098.36\u00a0nM against MCF\u20107 (hormone receptor\u2010positive breast cancer), 15.08\u00a0\u00b1\u00a094.36\u00a0nM against MDA\u2010MB\u2010231 (triple\u2010negative breast cancer), and 60.89\u00a0\u00b1\u00a070.58\u00a0nM against A549 (lung cancer). ADMET analysis confirmed high gastrointestinal absorption, favorable drug\u2010likeness, and lack of blood\u2010brain barrier permeability. In addition, DFT studies indicated an optimal HOMO\u2013LUMO energy gap (0.15816\u00a0eV), chemical hardness (0.16189\u00a0eV), and strong molecular interactions corroborated by MEP analysis. Collectively, these findings establish RO5126766 as a potent and selective MEK1\/2 inhibitor, demonstrating significant potential as a targeted therapeutic agent for aggressive and treatment\u2010resistant cancers.<\/jats:p>","DOI":"10.1002\/cbdv.202402907","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T22:45:09Z","timestamp":1741733109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated Computational and Experimental Insights Into MEK1\/2 Inhibitors: Structural Validation, Docking, ADMET, Molecular Dynamics, and Anticancer Evaluation"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2763-5757","authenticated-orcid":false,"given":"Rohit","family":"Pal","sequence":"first","affiliation":[{"name":"Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry Acharya and BM Reddy College of Pharmacy  Bengaluru Karnataka 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