8K5W

Crystal structure of human proMMP-9 catalytic domain in complex with inhibitor

8K5W の概要

• エントリーDOI: 10.2210/pdb8k5w/pdb
• 分子名称: Matrix metalloproteinase-9, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: mmp-9, 92 kda gelatinase, 92 kda type iv collagenase, gelatinase b, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55869.16

構造登録者

Kamitani, M.,Mima, M.,Nishikawa-Shimono, R. (登録日: 2023-07-24, 公開日: 2023-12-06)

主引用文献

Nishikawa-Shimono, R.,Kuwabara, M.,Fujisaki, S.,Matsuda, D.,Endo, M.,Kamitani, M.,Futamura, A.,Nomura, Y.,Yamaguchi-Sasaki, T.,Yabuuchi, T.,Yamaguchi, C.,Tanaka-Yamamoto, N.,Satake, S.,Abe-Sato, K.,Funayama, K.,Sakata, M.,Takahashi, S.,Hirano, K.,Fukunaga, T.,Uozumi, Y.,Kato, S.,Tamura, Y.,Nakamori, T.,Mima, M.,Mishima-Tsumagari, C.,Nozawa, D.,Imai, Y.,Asami, T.
Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.
Bioorg.Med.Chem.Lett., 97:129541-129541, 2023

PubMed Abstract: Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.

PubMed: 37952596
DOI: 10.1016/j.bmcl.2023.129541

実験手法

X-RAY DIFFRACTION (2 Å)