Structure-based pharmacophore modeling for precision inhibition of mutant ESR2 in breast cancer: A systematic computational approach.

Abstract

Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand-binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in-house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild-type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of -8.26, -5.73, -10.80, and -8.42 kcal/mol, respectively, along with the control -7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM-GBSA analysis. Based on MD simulations and MM-GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy.