Computational Screening of Dietary Flavonoids Against Aromatase (CYP19A1) as Potential Anti-Breast-Cancer Agents: An Integrated Molecular Docking, ADMET, DFT, and Molecular-Dynamics Study

Abstract

Background: Aromatase (CYP19A1), the rate-limiting enzyme of estrogen biosynthesis, is a validated therapeutic target in hormone-dependent breast cancer, and dietary flavonoids abundant in South Indian diets have long been proposed as complementary chemopreventive scaffolds. Objective: To computationally screen and prioritize thirteen dietary flavonoids as candidate aromatase inhibitors using an integrated in silico workflow benchmarked against the clinical inhibitor letrozole. Methods: A curated library of thirteen flavonoids and letrozole (reference) was subjected to molecular docking against human aromatase (CYP19A1), with five poses per ligand and profiling of protein-ligand interactions, heme contact, drug-likeness (Lipinski rule-of-five), ADMET prediction, and density-functional-theory (DFT) frontier-orbital descriptors. The three highest-priority complexes were advanced to 100 ns molecular-dynamics (MD) simulation with MM-GBSA binding-free-energy estimation. Results: Best docking binding energies for the flavonoids ranged from -9.05 to -8.00 kcal/mol, closely approaching letrozole (-9.28 kcal/mol). Rutin (-9.05), myricetin (-8.94), and luteolin (-8.92 kcal/mol) were the strongest binders, engaging conserved active-site residues (Asp309, Thr310, Met374, Phe134, Val370) with recurrent heme-environment contacts. Integrating docking rank with drug-likeness, ADMET flags, and DFT reactivity, myricetin and luteolin emerged as high-priority candidates, whereas rutin-despite the best flavonoid score-carried three Lipinski violations and low predicted gastrointestinal absorption. Across 100 ns MD, all three complexes were stable; MM-GBSA free energies were -56.58 (rutin), -49.47 (luteolin), and -37.73 kcal/mol (myricetin), with hydrogen-bond occupancies of 68.7%, 37.1%, and 51.5%, respectively. Conclusion: Dietary flavonoids, notably luteolin and myricetin, are computationally credible aromatase-binding scaffolds warranting biochemical and cell-based validation.