Insight into the structural determinants of imidazole scaffold-based derivatives as p38 MAP kinase inhibitors by computational explorations.
P38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-α and interleukin-1β pathways, and thus the inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Presently, a combined study of three-dimensional quantitative structure-activity relationship, molecular docking and molecular dynamics (MD) was undertaken to explore the structural insights of 174 2-thioimidazole compounds influencing the p38α inhibitory activities. Both the ligand-based resultant comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models exhibited satisfactory predictability (with Q(2)=0.475, R(2)(ncv)=0.774, R(2)(pre)=0.668 and Q(2)=0.504, R(2)(ncv)=0.745, R(2)(pre)=0.709, respectively). Furthermore, good consistency was observed between the 3D-QSAR models, docking and MD results. Our findings are: i) hydrogen bonding and steric size of the molecules play crucial roles in the mechanisms of action that a medium-sized bulky substituent on the 2-position, an electropositive H-bond donor substituent on the 6-position of the pyridine ring are favorable for increasing the inhibition activity; ii) 2- Thioimidazole derivatives may bind to the p38α kinase with a "lobster" active conformation, which is fixed by four hydrogen bonds they formed with the adjacent residues (Lys53, Gly110, Met109 and Ala157) and two hydrophobic interactions (in hydrophobic pockets I and II respectively) in p38α binding site. These models and the derived information may afford valuable clues for design of new potent p38α inhibitors.
Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, 116024, Liaoning, China.
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Huang
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Li
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Ren
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Wang
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Shao
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Zhang
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Li
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Yang
D001665:Binding Sites; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; C029899:imidazole; D048051:p38 Mitogen-Activated Protein Kinases