Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors

Bioorg Med Chem Lett. 2005 Aug 15;15(16):3787-90. doi: 10.1016/j.bmcl.2005.05.079.

Abstract

A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.

Publication types

  • Comparative Study

MeSH terms

  • Binding Sites
  • Chelating Agents / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Matrix Metalloproteinase 12
  • Metalloendopeptidases / antagonists & inhibitors*
  • Metalloendopeptidases / chemistry
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Zinc / chemistry

Substances

  • Chelating Agents
  • Enzyme Inhibitors
  • Metalloendopeptidases
  • MMP12 protein, human
  • Matrix Metalloproteinase 12
  • Zinc