Open AccessStructure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
Author(s) -
Jun Yong Choi,
Rita Fuerst,
Anna M. Knapinska,
Alexander B. Taylor,
Lyndsay Smith,
Xiaoguang Cao,
P. John Hart,
Gregg B. Fields,
William Roush
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b00514
Subject(s) - chemistry , pharmacophore , stereochemistry , chelation , matrix metalloproteinase , active site , binding site , lead compound , matrix metalloproteinase inhibitor , molecular model , combinatorial chemistry , molecule , chemical synthesis , small molecule , hydroxamic acid , enzyme inhibitor , enzyme , biochemistry , in vitro , organic chemistry
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 Zn 2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn 2+ 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 Zn 2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.