Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

J Med Chem. 2017 Jul 13;60(13):5816-5825. doi: 10.1021/acs.jmedchem.7b00514. Epub 2017 Jun 27.


We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Matrix Metalloproteinase 13 / chemistry
  • Matrix Metalloproteinase 13 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Models, Molecular
  • Zinc / chemistry


  • Chelating Agents
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 13
  • Zinc