A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases

Eur J Med Chem. 2009 Aug;44(8):3266-71. doi: 10.1016/j.ejmech.2009.03.034. Epub 2009 Apr 5.

Abstract

A structure-based virtual screening survey was used to identify potential inhibitors of the human M14 family of metallocarboxypeptidases. A good correlation between docking energy scores and measured K(i) values was observed, indicating an efficient performance of the screening procedure. Among various compounds displaying K(i) values in the low micromolar range, N-(3-chlorophenyl)-4-((5-(3-methoxybenzylthio)-1,3,4-oxadiazol-2-yl)methyl)thiazol-2-amine emerged as the most powerful inhibitor for human carboxypeptidase B (CPB). According to molecular docking, this compound fits into CPB active site cleft through coordination of the catalytic zinc ion with the 1,3,4-oxadiazole moiety. This represents a novel five-membered heterocyclic type of inhibitor for disease-linked metallocarboxypeptidases and an interesting lead for further development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxypeptidase B / antagonists & inhibitors*
  • Carboxypeptidase B / chemistry
  • Carboxypeptidase B / metabolism
  • Carboxypeptidases A / antagonists & inhibitors*
  • Carboxypeptidases A / chemistry
  • Carboxypeptidases A / metabolism
  • Computational Biology
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / metabolism
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Lepidoptera / enzymology
  • Models, Molecular
  • Molecular Conformation
  • Oxazoles / chemistry
  • Oxazoles / metabolism
  • Oxazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Oxazoles
  • Carboxypeptidases A
  • Carboxypeptidase B