Design and Computational Analysis of 2-Chlorobenzoylated Quercetin Derivatives as Inhibitors of Estrogen Receptor Alpha

Breast cancer remains a leading cause of mortality in women, highlighting the need for novel therapeutics. Quercetin, a natural flavonoid, shows anticancer potential but suffers from poor pharmacokinetics. To enhance its activity, 23 quercetin derivatives were designed as the flavonoid derivatives (FLD) series and evaluated using an integrated in silico workflow, including Lipinski’s rule-of-five assessment, molecular docking against the estrogen receptor alpha (ERα; PDB ID: 3ERT), and ADMET prediction. Based on docking scores and favorable ADMET profiles, FLD-4, FLD-5, and FLD-6 were selected for 100 ns molecular dynamics simulations. FLD-4 exhibited the highest stability with an average RMSD of approximately 0.30 nm, while FLD-6 showed larger fluctuations (0.45 nm). SASA analysis revealed more compact structures for FLD-4 and the control ligand (131–133 nm2) compared to quercetin and FLD-6. RMSF analysis confirmed reduced terminal residue flexibility for FLD-4 and FLD-5 ( 1.0 nm. MM-PBSA analysis further identified FLD-4 as the most stable complex (−205.409 ± 17.844 kJ/mol). Collectively, these results indicate that FLD-4 forms a stable, compact complex with improved binding affinity and drug-likeness, supporting its potential as a lead compound for flavonoid-based breast cancer therapy.