Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design

J. M. Chen, F. C. Nelson, J. I. Levin, D. Mobilio, J. F. Moy, R. Nilakantan, A. Zask, R. Powers

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1' pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 μM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1' pocket of MMP-13 which is the basis of its selectivity against MMP-1, MMP-9, and TACE. A strategy utilizing this information was devised for designing new inhibitors that showed enhanced selectivity toward MMP-13. Our design strategy combined the critical selectivity features of CL-82198 with the known potency features of a nonspecific MMP inhibitor (WAY-152177) to generate a potent and selective MMP-13 inhibitor (WAY-170523). WAY-170523 has an IC50 of 17 nM for MMP-13 and showed >5800-, 56-, and >500-fold selectivity against MMP-1, MMP-9, and TACE, respectively.

Original languageEnglish (US)
Pages (from-to)9648-9654
Number of pages7
JournalJournal of the American Chemical Society
Volume122
Issue number40
DOIs
StatePublished - Oct 11 2000
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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