8K4Z

Crystal structure of human MMP-7 in complex with inhibitor

8K4Z の概要

• エントリーDOI: 10.2210/pdb8k4z/pdb
• 分子名称: Matrilysin, Inhibitor, CALCIUM ION, ... (7 entities in total)
• 機能のキーワード: matrilysin, matrin, matrix metalloproteinase-7, pump-1 protease, uterine metalloproteinase, 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: 20545.28

構造登録者

Kamitani, M.,Mima, M.,Oka, Y. (登録日: 2023-07-20, 公開日: 2024-04-17, 最終更新日: 2025-02-26)

主引用文献

Oka, Y.,Abe-Sato, K.,Tabuse, H.,Yasukawa, Y.,Yahara, T.,Nishimoto, T.,Kamitani, M.,Fukunaga, T.,Ochiai, N.,Kumasaka-Abe, T.,Hitaka, K.,Gunji, E.,Ohara, H.,Takeda, T.,Kojima, N.,Asami, T.
Discovery of TP0628103: A Highly Potent and Selective MMP-7 Inhibitor with Reduced OATP-Mediated Clearance Designed by Shifting Isoelectric Points.
J.Med.Chem., 67:1406-1420, 2024

PubMed Abstract: Matrix metalloproteinase-7 (MMP-7) has been shown to play an important role in pathophysiological processes such as cancer and fibrosis. We previously discovered selective MMP-7 inhibitors by molecular hybridization and structure-based drug design. However, the systemic clearance (CL) of the biologically active lead compound was very high. Because our studies revealed that hepatic uptake by organic anion transporting polypeptide (OATP) was responsible for the high CL, we found a novel approach to reducing their uptake based on isoelectric point (IP) values as an indicator for substrate recognition by OATP1B1/1B3. Our "IP shift strategy" to adjust the IP values culminated in the discovery of TP0628103 (), which is characterized by reduced OATP-mediated hepatic uptake and CL. Our - extrapolation of OATP-mediated clearance and the "IP shift strategy" provide crucial insights for a new medicinal chemistry approach to reducing the systemic clearance of OATP1B1/1B3 substrates.

PubMed: 38214909
DOI: 10.1021/acs.jmedchem.3c01967

実験手法

X-RAY DIFFRACTION (1.7 Å)