Selectivity Requirement of Estrogen Receptor Ligands: Modeling of Furan and Pyrazole Derivatives Md Ataul Islam and Achintya Saha

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 (Rα=0.871, Qα=0.807, R 2 pred-α=0.739; R 2 β=0.906, Q 2 β=0.876, R 2 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: Rα=0.990, Q 2 α=0.635, R 2 pred-α=0.646; R 2 β=0.970, Q 2 β=0.544, R 2 pred-β=0.646) are obtained with importance of steric and electrostatic fields for both subtypes, whereas similarity analysis models (CoMSIA: Rα=0.995, Q 2 α=0.691, R 2 pred-α=0.580; Rβ=0.956, Q 2 β=0.663, R 2 pred-β=0.693) revealed that steric, hydrophobic and hydrogen bond (HB) acceptor are prime factors for both αand β-subtypes. Space modeling studies (Rα=0.941, Q 2 α=0.872, R 2 pred-α=0.721; R 2 β=0.867, Q 2 β=0.831, R 2 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.