Computer Aided Drug Design Of P38Mapk Inhibitors

P38MAPK plays a vital role in the inflammation whose inhibitors provide effective approach for the treatment of inflammatory diseases. Presently, a combined study of three-dimensional quantitative structure-activity relationship (3D-QSAR), pharmacophore model, molecular docking and molecular dynamics (MD) were undertaken to explore the structural insights of1742-thioimidazoles and the mechanism of ligand-receptor actions. Based on the p38a (activity A) and TNF-a (activity B) inhibitory activity, both the resultant3D-QSAR models exhibited satisfactory predictability. Activity A:Q2=0.475, R2ncv=0.774, R2Pre=0.668for comparative molecular field analysis (CoMFA) and Q2=0.504, R2ncv=0.745, R2pre=0.709for comparative molecular similarity index analysis (CoMSIA); Activity B: Q2=0.561, R2ncy=0.810, R2pre=0.893for CoMFA and Q2=0.579, R2ncv=0.843, R2pre=0.926for CoMSIA. Good consistency was observed between the contour maps, pharmacophore model, docking and MD results, indicating the reasonability of the obtained models.Our findings are:(1) Important modification requirements for effective dual antagonists of activity A and B:for2-position of pyridine ring (R1), medium-sized sterically hydrophobic substituents would be favorable; for2-position of pyridine ring (R2), electropositive hydrophilic groups and H-bond donor substituents would be favorable; for6-position of pyridine ring, electropositive H-bond donors would be favorable; for1-position of imidazole core, electropositive groups would be favorable; for2-position of imidazole core, electronegative H-bond donors would be favorable, while sterically groups would lead to a decrease of activity; for3-position of imidazole core, H-bond acceptors would be favorable.(2) H-bonds and hydrophobic interaction play crucial roles in the mechanism of actions for activity A and B.(3) Ten essential features required for activity B, defined as two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites.(4) four H-bonds and two hydrophobic interactions strengthen the binding affinity between the ligand and p38a kinase, and2-thioimidazole derivatives may bind to the p38a kinase with a "lobster" active conformation. These models and the derived information may afford valuable clues for design of new potent p38MAPK inhibitors.