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 PubMedBased on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1. Structure-based design, synthesis, and binding mode analysis of novel and potent chymase inhibitors.,Futamura-Takahashi J, Tanaka T, Sugawara H, Iwashita S, Imajo S, Oyama Y, Muto T Bioorg Med Chem Lett. 2018 Jan 15;28(2):188-192. doi: 10.1016/j.bmcl.2017.11.031., Epub 2017 Nov 16. PMID:29191554[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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