8h78
Crystal structure of human MMP-2 catalytic domain in complex with inhibitorCrystal structure of human MMP-2 catalytic domain in complex with inhibitor
Structural highlights
Publication Abstract from PubMedMatrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule-peptide hybrid 1, the tripeptide linker 5-aminopentanoic acid [Ape(5)]-Glu-Asp of 1 was replaced by a shorter linker (gamma-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1' pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (K(i) = 0.034 nM) and >/=2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t(1/2) = 265 min). Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase-2 Inhibitor with a Phenylbenzamide-Pentapeptide Hybrid Scaffold.,Takeuchi T, Nomura Y, Tamita T, Nishikawa R, Kakinuma H, Kojima N, Hitaka K, Tamura Y, Kamitani M, Mima M, Nozoe A, Hayashi M J Med Chem. 2023 Jan 12;66(1):822-836. doi: 10.1021/acs.jmedchem.2c01698. Epub , 2023 Jan 3. PMID:36595440[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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