Inhibitor fingerprinting of matrix metalloproteases using a combinatorial peptide hydroxamate library

Mahesh Uttamchandani, Jun Wang, Junqi Li, Mingyu Hu, Hongyan Sun, Kitty Y.T. Chen, Kai Liu, Shao Q. Yao

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

We report the inhibitor fingerprints of seven matrix metalloproteases, representing all five established families of this important class of enzymes, against a highly diversified small-molecule library. A total of 1400 peptide hydroxamates were individually prepared by systematically permuting both natural and unnatural amino acids across the P′1, P′ 2, and P′3 positions, thereby generating an inhibitor library with three-pronged structural diversity. High-throughput screenings were efficiently conducted in microtiter plate format, providing a rapid and quantitative determination of inhibitor potency across the panel of enzymes. Despite similarities in substrate preferences and structural homologies within this class of enzymes, our findings revealed distinct patterns of inhibition for each MMP against varied chemical scaffolds. The resulting inhibitor fingerprints readily facilitated the identification of inhibitors with good potency as well as desirable selectivity, potentially minimizing adverse effects when developing such leads into candidate drugs. The strategy also offers a novel method for the functional classification of matrix metalloproteases, on the basis of the characteristic profiles obtained using the diverse set of inhibitors. This approach thus paves the way forward in lead identification by providing a rapid and quantitative method for selectivity screening at the outset of the drug discovery process.

Original languageEnglish (US)
Pages (from-to)7848-7858
Number of pages11
JournalJournal of the American Chemical Society
Volume129
Issue number25
DOIs
StatePublished - Jun 27 2007
Externally publishedYes

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Inhibitor fingerprinting of matrix metalloproteases using a combinatorial peptide hydroxamate library'. Together they form a unique fingerprint.

  • Cite this