4K2Y

Crystal Structure of Human Chymase in Complex with Fragment Inhibitor 6-chloro-1,3-dihydro-2H-indol-2-one

Summary for 4K2Y

• Entry DOI: 10.2210/pdb4k2y/pdb
• Related: 3S0N 4K5Z 4K60 4K69
• Descriptor: Chymase, ZINC ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: serine protease, glycosylated, mast cells, secreted, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 25446.07

Authors

Collins, B.K.,Padyana, A.K. (deposition date: 2013-04-09, release date: 2013-05-29, Last modification date: 2020-07-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)