jm7b00514_si_003.pdb (211.91 kB)
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
dataset
posted on 2017-06-26, 20:44 authored by Jun Yong Choi, Rita Fuerst, Anna M. Knapinska, Alexander B. Taylor, Lyndsay Smith, Xiaohang Cao, P. John Hart, Gregg B. Fields, William R. RoushWe 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.