Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Eur J Med Chem. 2017 Sep 29;138:661-668. doi: 10.1016/j.ejmech.2017.06.045. Epub 2017 Jun 24.

Abstract

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

Keywords: Cyclooxygenase-1 inhibition; Diarylisoxazole; Mofezolac; Molecular modelling; P6; X-ray crystallography.

MeSH terms

  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole
  • Cyclooxygenase Inhibitors
  • Isoxazoles
  • Cyclooxygenase 1
  • mofezolac