Potent, selective pyrone-based inhibitors of stromelysin-1 |
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Authors: | Puerta David T Mongan John Tran Ba L McCammon J Andrew Cohen Seth M |
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Institution: | 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. |
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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. |
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