3D-QSAR and molecular docking studies on fused pyrazoles as p38α mitogen-activated protein kinase inhibitors.
The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulting model of CoMFA and CoMSIA exhibited good r(2) (cv) values of 0.725 and 0.609, and r(2) values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38α MAPK. We have accordingly designed a series of novel p38α MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38α MAPK inhibitors.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong, China; E-Mails: lanpingsmzh@126.com (P.L.); huangzhijian0505@gmail.com (Z.-J.H.); sunjunrong1986@yahoo.com.cn (J.-R.S.).
Ping
P
Lan
Zhi-Jian
ZJ
Huang
Jun-Rong
JR
Sun
Wei-Min
WM
Chen
D000595:Amino Acid Sequence; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048308:Mitogen-Activated Protein Kinase 14