4k60
From Proteopedia
Crystal Structure of Human Chymase in Complex with Fragment 6-bromo-1,3-dihydro-2H-indol-2-one
Structural highlights
FunctionCMA1_HUMAN Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. Publication Abstract from PubMedChymase 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. Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.,Taylor SJ, Padyana AK, Abeywardane A, Liang S, Hao MH, De Lombaert S, Proudfoot JR, Farmer BS, Li X, Collins B, Albaugh DR, Martin L, Hill-Drzewi M, Pullen SS, Takahashi H J Med Chem. 2013 May 9. PMID:23659209[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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