Three-dimensional quantitative structure-activity relationship study on paullones as CDK inhibitors using CoMSIA and CoMFA

3D-QSAR studies were conducted on a series of paullones as CDK inhibitors u sing three-dimensional quantitative structure-activity relationship (3D-QSA R) methods. Two methods were compared: the widely used comparative molecula r field analysis (CoMFA) and the recently reported comparative molecular si milarity indices analysis (CoMSIA). Systematic variations of some parameter s in CoMSIA and CoMFA were performed to search for the best 3D-QSAR model. The computed results showed that the 3D-QSAR models from CoMSIA were clearl y superior to those from CoMFA. Using the best model from CoMSIA analysis, a significant cross-validated q(2) was obtained and the predicted biologica l activities of the five compounds in the test set were in good agreement w ith the experimental values. The correlation results obtained from CoMSIA w ere graphically interpreted in terms of field contribution maps allowing ph ysicochemical properties relevant for binding to be easily mapped back onto molecular structures. The features in the CoMSIA contour maps intuitively suggested where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity, which is very important for improving our understanding of the ligand-rece ptor interactions and in helping to design compounds with improved activity .