Molecular modelling and quantitative structure-activity relationship studies on the interaction of omeprazole with cytochrome P450 isozymes

Toxicology. 1998 Jan 16;125(1):31-44. doi: 10.1016/s0300-483x(97)00159-5.

Abstract

Molecular modelling of the anti-ulcerative agent, omeprazole, with the putative active sites of cytochromes P4503A4 and P4502C19, enzymes which are the major catalysts of omeprazole metabolism in man, are reported. Interactive docking of omeprazole in both CYP3A4 and CYP2C19 gives rise to binding orientations which are consistent with both the known sites of metabolism reported for these isoforms and with evidence from site-directed mutagenesis experiments on CYP2C19, a P450 associated with genetic polymorphism in human drug metabolism. The potential P450 enzymic interactions, inhibition and induction of omeprazole are discussed in the light of molecular modelling and QSAR (quantitative structure-activity relationship) studies on related compounds.

Publication types

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

MeSH terms

  • Anti-Ulcer Agents / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Humans
  • Isoenzymes / metabolism*
  • Liver / metabolism*
  • Mixed Function Oxygenases / metabolism
  • Models, Molecular
  • Omeprazole / metabolism*
  • Structure-Activity Relationship

Substances

  • Anti-Ulcer Agents
  • Isoenzymes
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Omeprazole