7D5U

BACE2 xaperone complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(prop-1-yn-1-yl)-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide

7D5U の概要

• エントリーDOI: 10.2210/pdb7d5u/pdb
• 分子名称: Beta-secretase 2, xaperone, N-[3-[(9S)-7-azanyl-2,2-bis(fluoranyl)-9-prop-1-ynyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: bace2, hydrolase, hydrolase-immune system complex, hydrolase/immune system
• 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: 54665.25

構造登録者

Fujimoto, K.,Yoshida, S.,Tadano, G.,Asada, N.,Fuchino, K.,Suzuki, S.,Matsuoka, E.,Yamamoto, T.,Yamamoto, S.,Ando, S.,Kanegawa, N.,Tonomura, Y.,Ito, H.,Moechars, D.,Rombouts, F.J.R.,Gijsen, H.J.M.,Kusakabe, K.I. (登録日: 2020-09-28, 公開日: 2021-03-31, 最終更新日: 2024-10-16)

主引用文献

Fujimoto, K.,Yoshida, S.,Tadano, G.,Asada, N.,Fuchino, K.,Suzuki, S.,Matsuoka, E.,Yamamoto, T.,Yamamoto, S.,Ando, S.,Kanegawa, N.,Tonomura, Y.,Ito, H.,Moechars, D.,Rombouts, F.J.R.,Gijsen, H.J.M.,Kusakabe, K.I.
Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2.
J.Med.Chem., 64:3075-3085, 2021

PubMed Abstract: BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine with improved selectivity. Further optimization efforts led to the discovery of compound with high selectivity. The cocrystal structures of , a close analogue of , bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity.

PubMed: 33719429
DOI: 10.1021/acs.jmedchem.0c01858

実験手法

X-RAY DIFFRACTION (2.04 Å)