Structure-based QSAR, molecule design and bioassays of protease-activated receptor 1 inhibitors.

摘要: Quantitative structure-activity relationship (QSAR) studies were performed on a series of protease-activated receptor 1 (PAR1) inhibitors to identify the key structural features responsible for their biological activity. Induced-fit docking (IFD) was used explore active mechanisms all PAR1 at pocket PAR1, and best plausible conformation determined by IFD further QSAR studies. Based conformation, structure-based descriptors ligand incorporating ligand-receptor interaction calculated. The random forest method select important build 2D-QSAR model. results model gave squared correlation coefficient (R2) 0.937, prediction (R2pred) 0.845 mean square error (MSE) 0.056. Furthermore, 3D-QSAR developed via topomer comparative molecular field analysis (Topomer CoMFA), resulting in an R2 0.938, cross-validated Q2 0.503 R2pred 0.758. model, Topomer search virtual screening fragment lead-like from National Cancer Institute (NCI) database, which contains 260,000 molecules. Eighty-two compounds designed with different fragments, four these selected testing. All showed inhibitory potency against PAR1.