4K69

Crystal Structure of Human Chymase in Complex with Fragment Linked Benzimidazolone Inhibitor: (3S)-3-{3-[(6-bromo-2-oxo-2,3-dihydro-1H-indol-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}hexanoic acid

4K69 の概要

• エントリーDOI: 10.2210/pdb4k69/pdb
• 関連するPDBエントリー: 3S0N 4K2Y 4K5Z 4K60
• 分子名称: Chymase, ZINC ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: serine protease, glycosylated, mast cells, secreted, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 25816.21

構造登録者

Collins, B.K.,Padyana, A.K. (登録日: 2013-04-15, 公開日: 2013-05-29, 最終更新日: 2024-10-16)

主引用文献

Taylor, S.J.,Padyana, A.K.,Abeywardane, A.,Liang, S.,Hao, M.H.,De Lombaert, S.,Proudfoot, J.,Farmer, B.S.,Li, X.,Collins, B.,Martin, L.,Albaugh, D.R.,Hill-Drzewi, M.,Pullen, S.S.,Takahashi, H.
Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.
J.Med.Chem., 56:4465-4481, 2013

PubMed Abstract: Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.

PubMed: 23659209
DOI: 10.1021/jm400138z

実験手法

X-RAY DIFFRACTION (1.5 Å)