Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

Abstract

Molecular modeling studies were performed to develop a predictive common pharmacophore hypothesis (CPH) and use it for alignment in three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies using CoMFA and CoMSIA, with a diverse set of 80 β3-adrenergic receptor (β3-AR) agonists. Using PHASE (Pharmacophore Alignment and Scoring Engine) six-point CPH with one acceptor, one negative charge, one positive charge, and three rings, features were derived for pharmacophore-based alignment of molecules. CPH was selected by correlating the observed and estimated activity for the training set and test set of molecules using partial least squares analysis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good “predictive” r 2 value of 0.6635 and 0.8665 for CoMFA and CoMSIA, respectively. The 3D contour CoMFA/CoMSIA maps provided an interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects at different positions of the biphenyl benzoic acid derivatives. CPH can also provide a powerful template for virtual screening and design of new β3-AR agonists.