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

Jun Yong Choi, Rita Fuerst, Anna M. Knapinska, Alexander B. Taylor, Lyndsay Smith, Xiaohang Cao, Peter J Hart, Gregg B. Fields, William R. Roush

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5816-5825
Number of pages10
JournalJournal of Medicinal Chemistry
Volume60
Issue number13
DOIs
StatePublished - Jul 13 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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