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

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 field 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 five 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 understanding of vital interactions between the inhibitors and Weel kinase. As a result, we have identified some key features in the 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones responsible for the Weel inhibitory activity that may be used to design more potent 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones and predict their activity prior to synthesis.

Graphical abstractMolecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA were applied to a set of novel 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Checkpoint Kinase Weel inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide