In Silico ADMET Profiling, Drug-Likeness Evaluation, and Molecular Docking Studies of a Novel Series of Chalcone Derivatives as Potent Anticancer Agents Targeting the 7MSX Protein

The relentless progression of oncological diseases and the concurrent emergence of multidrug-resistant cancer phenotypes necessitate the continuous and aggressive discovery of novel therapeutic pharmacophores. Chalcones (1,3-diaryl-2-propen-1-ones), a distinct subclass of naturally occurring and synthetic flavonoids, have garnered immense attention in medicinal chemistry due to their highly reactive alpha, beta-unsaturated carbonyl system and privileged structural scaffold, which exhibit profound cytotoxic and apoptotic activities against various malignant cell lines. In this comprehensive computational investigation, a unified series of ten structurally diverse chalcone derivatives (AM-01 to AM-10) was systematically evaluated for their anticancer potential targeting the critical oncogenic protein designated by PDB ID: 7MSX. Advanced molecular docking simulations were executed utilizing AutoDock Vina to precisely elucidate the thermodynamic binding affinities, stereochemical orientations, and non-covalent biomolecular interactions within the hydrophobic active site of the receptor. The synthesized derivatives demonstrated highly negative and favorable binding free energies ranging from -7.0 kcal/mol to -8.9 kcal/mol. Notably, compound AM-10 exhibited the maximum binding affinity (-8.9 kcal/mol), stabilized by robust hydrogen bonding with GLU268 and distinct pi-cation interactions with ARG264. To ascertain the pharmacological viability of these compounds, exhaustive in silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling was conducted. All sixteen derivatives exhibited zero violations of Lipinski’s Rule of Five (RO5), alongside optimal Topological Polar Surface Area (TPSA) values, indicating exceptional predicted gastrointestinal absorption and ideal lipophilicity (LogP values between 2.85 and 4.25). Furthermore, toxicity predictive models confirmed an absence of AMES mutagenicity and minimal hepatotoxicity. Consequently, this study establishes the AM-series chalcones, particularly AM-08 and AM-10, as highly viable, safe, and potent lead candidates warranting imminent in vitro and in vivo translational oncology studies.