Structure-based QSAR, molecule design and bioassays of protease-activated receptor 1 inhibitors.
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 to explore the active mechanisms of all PAR1 inhibitors at the active pocket of PAR1, and the best plausible conformation was determined by IFD for further QSAR studies. Based on the best plausible conformation, structure-based descriptors and ligand descriptors incorporating the ligand-receptor interaction were calculated. The random forest method was used to select important descriptors and build the 2D-QSAR model. The results of the 2D-QSAR model gave a squared correlation coefficient (R2) of 0.937, a prediction squared correlation coefficient (R2pred) of 0.845 and a mean square error (MSE) of 0.056. Furthermore, a 3D-QSAR model was developed via topomer comparative molecular field analysis (Topomer CoMFA), resulting in an R2of 0.938, a cross-validated Q2of 0.503 and a R2predof 0.758. Based on the developed QSAR model, Topomer search was used for virtual screening of the R2 fragment in lead-like inhibitors from the National Cancer Institute (NCI) database, which contains 260,000 molecules. Eighty-two compounds were designed with different R2 fragments, and four of these compounds were selected for further biological testing. All four compounds showed inhibitory potency against PAR1.
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin 300071 , China.
Weilong
W
Zhong
b Tianjin Institute of Industrial Biotechnology , Chinese Academy of Sciences , Tianjin 300000 , China.
Pi
P
Liu
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin 300071 , China.
Qiang
Q
Zhang
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin 300071 , China.
Dongmei
D
Li
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin 300071 , China.|b Tianjin Institute of Industrial Biotechnology , Chinese Academy of Sciences , Tianjin 300000 , China.|c Pharmaceutical Intelligence Platform, Tianjin Joint Academy of Biomedicine and Technology , Tianjin 300457 , China.
Jianping
J
Lin
D001681:Biological Assay / Q000379:methods; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D010975:Platelet Aggregation Inhibitors
D004791:Enzyme Inhibitors; D008024:Ligands; D010975:Platelet Aggregation Inhibitors
Topomer CoMFA; induced-fit docking; protease-activated receptor 1 inhibitors; quantitative structure–activity relationship; random forest