Nitro as a novel zinc-binding group in the inhibition of carboxypeptidase A

Bioorg Med Chem. 2008 Apr 1;16(7):3596-601. doi: 10.1016/j.bmc.2008.02.010. Epub 2008 Feb 8.

Abstract

2-Substituted 3-nitropropanoic acids were designed and synthesized as inhibitors against carboxypeptidase A (CPA). (R)-2-Benzyl- 3-nitropropanoic acid showed a potent inhibition against CPA (K(i)=0.15 microM). X-ray crystallography discloses that the nitro group well mimics the transition state occurred in the hydrolysis catalyzed by CPA, that is, an O,O'-bidentate coordination to the zinc ion and the two respective hydrogen bonds with Glu-270 and Arg-127. Because the nitro group is a planar species, we proposed (R)-2-benzyl-3-nitropropanoic acid as a pseudo-transition-state analog inhibitor against CPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxypeptidases A / antagonists & inhibitors*
  • Carboxypeptidases A / metabolism*
  • Catalysis
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Nitrogen / chemistry*
  • Structure-Activity Relationship
  • Zinc / chemistry*

Substances

  • Enzyme Inhibitors
  • Carboxypeptidases A
  • Zinc
  • Nitrogen