Selectivity Requirement Of Estrogen Receptor Ligands: Modeling Of Furan And Pyrazole Derivatives

Abstract

Chemometric techniques become vital tools in the field of drug discovery by exploring chemical entity with optimistic efficacy. In the present work, a group of non-steroidal ligands, furan and pyrazole derivatives are considered to explore the structural requirement for binding selectivity to estrogen receptor (ER). 2D/3D quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies have been explored for this purpose. The classical QSAR models (R²_α=0.871, Q²_α=0.807, R²_pred-α=0.739; R²_β=0.906, Q²_β=0.876, R²_pred-β=0.764) explain that contribution of electronic charges of C₄, C₈ and C₂₄ for α-subtype, and C₂,  C₁₈ and C₂₄ of β-subtype are important for binding affinity. In 3D QSAR, field analysis models (CoMFA: R²_α=0.990, Q²_α=0.635, R²_pred-α=0.646; R²_β=0.970, Q²_β=0.544, R²_pred-β=0.646) are obtained with importance of steric and electrostatic fields for both subtypes, whereas similarity analysis models (CoMSIA: R²_α=0.995, Q²_α=0.691, R²_pred-α=0.580; R²_β=0.956, Q²_β=0.663, R²_pred-β=0.693) revealed that steric, hydrophobic and hydrogen bond (HB) acceptor are prime factors for both α- and β-subtypes. Space modeling studies (R²_α=0.941, Q²_α=0.872, R²_pred-α=0.721; R²_β=0.867, Q²_β=0.831, R²_pred-β=0.687) indicate the importance of HB donor and hydrophobic features for both subtypes and aromatic ring for β-subtype for selective binding to the ER. The pharmacophore features obtained from the models are substantiated by molecular docking studies.