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J Med Chem. 2017 Jul 13;60(13):5816-5825. doi: 10.1021/acs.jmedchem.7b00514. Epub 2017 Jun 27.

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.

Author information

1
Department of Chemistry, Scripps Florida , 130 Scripps Way, Jupiter, Florida 33458, United States.
2
Department of Chemistry & Biochemistry, Florida Atlantic University , Jupiter, Florida 33458, United States.
3
Department of Biochemistry and Structural Biology and the X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.

Abstract

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

PMID:
28653849
DOI:
10.1021/acs.jmedchem.7b00514
[Indexed for MEDLINE]

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