Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

Abstract

In this study, we explored the structural requirements of known estrogen receptor modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose, a group of nonsteroidal ligands 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide derivatives were collected from the literature to perform quantitative structure–activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R 2 = 0.857, se α = 0.370, Q 2 = 0.848, R pred− 2 = 0.675, s pα = 0.537; R 2 = 0.874, se β = 0.261, Q 2 = 0.859, R pred− 2 = 0.659, s pβ = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both α- and β-subtypes. The space modeling study (R 2 = 0.955, se α = 1.311, Q 2 = 0.932, R pred− 2 = 0.737, s pα = 0.497; R 2 = 0.885, se β = 1.328, Q 2 = 0.878, R pred− 2 = 0.769, s pβ = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas HB acceptor and aromatic ring were critical for α- and β-subtypes, respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking studies which provided the preferred orientation of ligands for effective interaction at the active site cavity.