5B5P

Crystal structure of the catalytic domain of MMP-13 complexed with 4-oxo-N-(3-(2-(1H-1,2,4-triazol-3-ylsulfanyl)ethoxy)benzyl)-3,4-dihydroquinazoline-2-carboxamide

Summary for 5B5P

• Entry DOI: 10.2210/pdb5b5p/pdb
• Related: 3WV1 3WV2 3WV3 5B5O
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: mmp-13, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P45452
• Total number of polymer chains: 2
• Total formula weight: 40076.02

Authors

Oki, H.,Tanaka, Y. (deposition date: 2016-05-13, release date: 2017-01-18, Last modification date: 2023-11-08)

Primary citation

Nara, H.,Kaieda, A.,Sato, K.,Naito, T.,Mototani, H.,Oki, H.,Yamamoto, Y.,Kuno, H.,Santou, T.,Kanzaki, N.,Terauchi, J.,Uchikawa, O.,Kori, M.
Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach
J. Med. Chem., 60:608-626, 2017

PubMed Abstract: On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.

PubMed: 27966948
DOI: 10.1021/acs.jmedchem.6b01007

Experimental method

X-RAY DIFFRACTION (1.6 Å)