8K4Z
Crystal structure of human MMP-7 in complex with inhibitor
Summary for 8K4Z
| Entry DOI | 10.2210/pdb8k4z/pdb |
| Descriptor | Matrilysin, Inhibitor, CALCIUM ION, ... (7 entities in total) |
| Functional Keywords | matrilysin, matrin, matrix metalloproteinase-7, pump-1 protease, uterine metalloproteinase, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 20545.28 |
| Authors | Kamitani, M.,Mima, M.,Oka, Y. (deposition date: 2023-07-20, release date: 2024-04-17, Last modification date: 2025-02-26) |
| Primary citation | 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 Cited by 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: 38214909DOI: 10.1021/acs.jmedchem.3c01967 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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