Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13

J Med Chem. 2011 Dec 8;54(23):8174-87. doi: 10.1021/jm201129m. Epub 2011 Nov 9.

Abstract

Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.

MeSH terms

  • Crystallography, X-Ray
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Matrix Metalloproteinase 13 / chemistry
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship

Substances

  • Indoles
  • Matrix Metalloproteinase Inhibitors
  • Recombinant Proteins
  • Matrix Metalloproteinase 13