The molecular basis for coxib inhibition of p38alpha MAP kinase

Bioorg Med Chem Lett. 2005 Aug 1;15(15):3506-9. doi: 10.1016/j.bmcl.2005.05.107.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Databases, Factual
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • p38 Mitogen-Activated Protein Kinases