Potent, selective pyrone-based inhibitors of stromelysin-1.
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.
Puerta
David T
DT
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.
Mongan
John
J
Tran
Ba L
BL
McCammon
J Andrew
JA
Cohen
Seth M
SM
D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011753:Pyrones; D019278:Matrix Metalloproteinase 3; D015032:Zinc