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 r²(pred) 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.
Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116023, China. yanli@dlut.edu.cn
Yan
Y
Li
Ming
M
Hao
Hong
H
Ren
Shuwei
S
Zhang
Xia
X
Wang
Ming
M
Ma
Guohui
G
Li
Ling
L
Yang
D000465:Algorithms; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009570:Nitriles / Q000737:chemistry*; D025341:Principal Component Analysis; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta