The molecular basis for coxib inhibition of p38alpha MAP kinase.
In this work, we present the results of two combined approaches, molecular docking and comparative molecular field analysis (CoMFA), to propose how the selective cyclooxygenase-2 inhibitor celecoxib could act as a p38 mitogen-activated protein (MAP) kinase inhibitor. The docking analysis revealed why celecoxib has a less favorable binding energy (DeltaG= -12.4kcal/mol) than the selective p38 MAP kinase (p38 MAPK) inhibitor, SB203580 (DeltaG= -22.2kcal/mol). The CoMFA results revealed unfavorable steric effects that can be related to the predicted lower p38 MAP kinase inhibitory activity of celecoxib. Additionally, FlexX and CoMFA results also suggested that etoricoxib, another selective COX-2 inhibitor, could inhibit p38 MAP kinase.
Sperandio da Silva
Gilberto M
GM
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, PO Box 68006, RJ 21944-971, Brazil.
Lima
Lidia M
LM
Fraga
Carlos A M
CA
Sant'Anna
Carlos M R
CM
Barreiro
Eliezer J
EJ
D000465:Algorithms; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016208:Databases, Factual; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048051:p38 Mitogen-Activated Protein Kinases