3D-QSAR studies of 8-substituted chromen-4-one-2-carboxylic acid derivatives as potent agonists for the orphan G protein-coupled receptor 35

Abstract

GPR35, an orphan G protein-coupled receptor, has attracted much attention as a novel therapeutic target for the treatment of diabetes, hypertension, etc. Recently, 8-substituted chromen-4-one-2-carboxylic acid derivatives were identified as potent and selective agonists for human GPR35. In the present study, the three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed for a series of 8-substituted chromen-4-one-2-carboxylic acid derivatives using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA techniques implemented in the SYBYL software packages. The statistically significant models were obtained with 30 compounds in training set by ligand-based atom-by-atom matching alignment, which were further validated by a test set of eight compounds. The CoMFA model resulted in cross-validated coefficient (q 2) value of 0.610 using 4 components, non-cross-validated coefficient (r 2) value of 0.918 with estimated F value of 69.917, and standard error of estimate (SEE) of 0.352. While the CoMSIA model combined with steric, electrostatic and hydrophobic fields were finally selected (q 2 = 0.646, r 2 = 0.800, F = 53.852, SEE = 0.489, N = 2). For the Topomer CoMFA model, the better statistics were obtained based on fragment units (q 2 = 0.746, r 2 = 0.979, F = 146.294, SEE = 0.175, N = 7). Furthermore, the contour maps obtained from 3D-QSAR studies were appraised for activity trends for the compounds analyzed. The results indicate that steric, electrostatic, and hydrophobic substituents play a significant role in the agonist activity. The data generated from the present study will further help design novel, potent, and selective agonists for GPR35.