Send to

Choose Destination
J Am Chem Soc. 2007 Jun 27;129(25):7848-58. Epub 2007 Jun 1.

Inhibitor fingerprinting of matrix metalloproteases using a combinatorial peptide hydroxamate library.

Author information

Department of Biological Sciences, National University of Singapore, Singapore 117543.


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 P1', P2', and P3' 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.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center