Insights from selective non-phosphinic inhibitors of MMP-12 tailored to fit with an S1' loop canonical conformation

J Biol Chem. 2010 Nov 12;285(46):35900-9. doi: 10.1074/jbc.M110.139634. Epub 2010 Sep 3.


After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S(1)' cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S(1)' specificity cavity, maximizing surface/volume ratios, without perturbing the S(1)' loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S(1)' loop conformation. The search for such compounds that fit precisely to preponderant S(1)' loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Assays
  • Humans
  • Kinetics
  • Matrix Metalloproteinase 12 / chemistry*
  • Matrix Metalloproteinase 12 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Models, Molecular
  • Molecular Structure
  • Phosphinic Acids / chemistry
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protein Conformation*
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Substrate Specificity


  • Matrix Metalloproteinase Inhibitors
  • Phosphinic Acids
  • Protease Inhibitors
  • Matrix Metalloproteinase 12