1 3D-QSAR studies of Checkpoint Kinase Weel inhibitors based on molecular docking, CoMFA and CoMSIA.pdf

Available online at European Journal of Medicinal Chemistry 43 (2008) 925e938 /locate/ejmech Original article 3D-QSAR studies of Checkpoint Kinase Weel inhibitors based on molecular docking, CoMFA and CoMSIA Ping Yi a,b, Xin Fang a,b, Minghua Qiu a,* a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China b Graduate School of the Chinese Academy of Sciences, Beijing 100039, China Received 6 February 2007; received in revised form 18 June 2007; accepted 21 June 2007 Available online 14 August 2007 Abstract Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on 97 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H )-dione inhibitors, based on molecular docking scores obtained by using GOLD 3.1, comparative molecular ?eld analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The docking results provided a reliable conformational alignment scheme for the 3D- QSAR model. Based on the docking conformations and alignments, highly predictive CoMFA and CoMSIA were obtained with cross-validated q2 value of 0.828 and 0.796, respectively, and non-cross-validated partial least-squares (PLS) analysis with the optimum components of ?ve showed a conventional r2 of 0.962 and 0.949, respectively. The predictive ability was validated by compounds that were not included in the training set. Furthermore, the CoMFA and CoMSIA model plots were mapped back to the binding sites of Checkpoint Kinase Weel, to get a better underst