Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening

Journal of Medicinal Chemistry
Daniel L CheneyE Scott Priestley

Abstract

A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.

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Citations

Jul 8, 2015·Journal of Medicinal Chemistry·E Scott PriestleyRuth R Wexler
Apr 26, 2016·Chemical Reviews·Stephen Boulton, Giuseppe Melacini
Oct 16, 2016·Journal of Medicinal Chemistry·Christopher N JohnsonDavid C Rees
Sep 11, 2016·Bioorganic & Medicinal Chemistry Letters·Vladimir Uladzimir LadziataE Scott Priestley
Jun 29, 2017·The Journal of Physical Chemistry. B·Fang-Yu Lin, Alexander D MacKerell
Dec 24, 2018·European Journal of Medicinal Chemistry·Kai SommerMatthias Rarey
Dec 21, 2016·ACS Medicinal Chemistry Letters·Nicholas R WurtzE Scott Priestley

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