Potent, selective pyrone-based inhibitors of stromelysin-1

David T Puerta; John Mongan; Ba L Tran; J Andrew McCammon; Seth M Cohen

doi:10.1021/ja054558o

Potent, selective pyrone-based inhibitors of stromelysin-1

J Am Chem Soc. 2005 Oct 19;127(41):14148-9. doi: 10.1021/ja054558o.

Authors

David T Puerta¹, John Mongan, Ba L Tran, J Andrew McCammon, Seth M Cohen

Affiliation

¹ Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, and Center for Theoretical Biological Physics, University of California-San Diego, La Jolla, CA 92093, USA.

PMID: 16218585
DOI: 10.1021/ja054558o

Abstract

In an effort to develop alternatives to hydroxamate-based matrix metalloproteinase inhibitors (MPIs), we have utilized the drug discovery program LUDI enhanced with the structural coordinates of a bioinorganic model complex. This method has yielded the first pyrone-based MPIs. The inhibitors demonstrate nanomolar potency against MMP-3 and are selective for MMP-3 over MMP-2 and MMP-1. We postulate that the potency and unusual selectivity profile of these MPI is attributable to the pyrone chelating group.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Matrix Metalloproteinase 3 / chemistry
Matrix Metalloproteinase Inhibitors*
Models, Molecular
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrones / chemical synthesis
Pyrones / chemistry*
Pyrones / pharmacology
Structure-Activity Relationship
Zinc / chemistry

Substances

Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Pyrones
Matrix Metalloproteinase 3
Zinc

Grants and funding

GM 72129-01/GM/NIGMS NIH HHS/United States