9H1C

Crystal structure of Angiotensin-1 converting enzyme C-domain in complex with dual ACE/NEP inhibitor AD014

これはPDB形式変換不可エントリーです。

9H1C の概要

• エントリーDOI: 10.2210/pdb9h1c/pdb
• 分子名称: Angiotensin-converting enzyme, CHLORIDE ION, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: angiotensin-1 converting enzyme, dual inhibitor, nep, metalloprotease, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 71249.76

構造登録者

Cozier, G.E.,Acharya, K.R. (登録日: 2024-10-09, 公開日: 2025-04-16)

主引用文献

Cozier, G.E.,Coulson, L.B.,Eyermann, C.J.,Basarab, G.S.,Schwager, S.L.,Chibale, K.,Sturrock, E.D.,Acharya, K.R.
Design of Novel Mercapto-3-phenylpropanoyl Dipeptides as Dual Angiotensin-Converting Enzyme C-Domain-Selective/Neprilysin Inhibitors.
J.Med.Chem., 68:7720-7736, 2025

PubMed Abstract: Dual angiotensin-converting enzyme (ACE) and neprilysin (NEP) inhibitors such as omapatrilat showed promise as potent treatments for hypertension but produced adverse effects due to their high affinity for both domains of ACE (nACE and cACE). This led to the search for compounds that retained NEP potency but selectively inhibit cACE, leaving nACE active to degrade other peptides such as bradykinin. Lisinopril-tryptophan (LisW) has previously been reported to have cACE selectivity. Three mercapto-3-phenylpropanoyl inhibitors were synthesized, combining features of omapatrilat and LisW to probe structural characteristics required for potent dual cACE/NEP inhibition. We report the synthesis of these inhibitors, enzyme inhibition data, and high-resolution crystal structures in complex with nACE and cACE. This provides valuable insight into factors driving potency and selectivity and shows that the mercapto-3-phenylpropanoyl backbone is significantly better for NEP potency than a P carboxylate. Future chemistry efforts could be directed at identifying alternative chemotypes for optimization of cACE/NEP inhibitors.

PubMed: 40168649
DOI: 10.1021/acs.jmedchem.5c00329

実験手法

X-RAY DIFFRACTION (1.8 Å)