Exploring the structure requirement for PKCθ inhibitory activity of pyridinecarbonitrile derivatives: an in silico analysis

Presently, an in silico modeling was carried out on a large series of 263 PKCθ inhibitors using 3D-QSAR, molecular docking and molecular dynamics (MD) simulations for the first time. Based on different alignment rules, several computational models were established with their statistical results compared. The resultant models derived from the database alignment exhibit satisfying internal and external predictive capabilities with q2 of 0.503, 0.616 and r2pred of 0.568, 0.602 for CoMFA and CoMSIA, respectively. The consistency of conclusion among 3D contour maps of CoMFA and CoMSIA, molecular docking and molecular dynamics proves the reliability of the developed models. The analysis of the 3D contour plots permits interesting conclusions about the effects of different substituent groups at different positions of the common scaffold. In addition, Leu461 and Asn509 have been identified as the key amino acid residues to form H-bond interaction with the ligand compound. The developed models will provide a clue to the design of novel PKCθ inhibitors.

The correlation plots of predicted versus actual pIC50 values using the training (black dot) and test (red asterisk) sets based on (A) CoMFA model and (B) CoMSIA model.Figure optionsDownload high-quality image (44 K)Download as PowerPoint slideHighlights
► 263 PKCθ inhibitors were studied using 3D-QSAR, docking and MD simulations.
► The consistency of conclusions among them proves the reliability of the models.
► The models might guide the design of novel PKCθ inhibitors.