Impact of mobility on structure-based drug design for the MMPs

Franklin J. Moy, Pranab K. Chanda, James Chen, Scott Cosmi, Wade Edris, Jeremy I. Levin, Thomas S. Rush, James Wilhelm, Robert Powers

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


Structure-based approaches for drug design generally do not incorporate solvent effects and dynamic information to predict inhibitor-binding affinity because of practical limitations. The matrix metalloproteinases (MMPs) have previously been demonstrated to exhibit significant mobility in their active sites. This dynamic characteristic significantly complicates the drug design process based on static structures, which was clearly observed for a class of hydroxamic acids containing a butynyl moiety. Compound 1 was expected to be selective against MMP-1 based on predicted steric clashes between the butynyl P1′ group and the S1′ pocket, but the observation of complex inhibitor dynamics in the NMR structure of MMP-1:1 provides an explanation for the low nanomolar binding to MMP-1.

Original languageEnglish (US)
Pages (from-to)12658-12659
Number of pages2
JournalJournal of the American Chemical Society
Issue number43
StatePublished - Oct 30 2002
Externally publishedYes

ASJC Scopus subject areas

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


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