Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening.

Autor:	Smith ST; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States., Cassada JB; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Von Bredow L; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States.; Institute for Drug Discovery, Leipzig University Medical School, Leipzig 04109, Germany., Erreger K; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Webb EM; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Trombley TA; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Kalbfleisch JJ; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Bender BJ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States., Zagol-Ikapitte I; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Kramlinger VM; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Bouchard JL; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Mitchell SG; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Tretbar M; Institute for Drug Discovery, Leipzig University Medical School, Leipzig 04109, Germany., Shoichet BK; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States., Lindsley CW; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States., Meiler J; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Institute for Drug Discovery, Leipzig University Medical School, Leipzig 04109, Germany., Hamm HE; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Mar 21; Vol. 7 (4), pp. 1086-1100. Date of Electronic Publication: 2024 Mar 21 (Print Publication: 2024).
DOI:	10.1021/acsptsci.3c00378
Abstrakt:	Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using a homology model of a difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated receptor 4 (PAR4) is activated by thrombin cleavage, revealing a tethered ligand that activates the receptor, making PAR4 a challenging target. A virtual screen of a make-on-demand chemical library yielded a one-hit compound. From the single-hit compound, we developed a novel series of PAR4 antagonists. Subsequent lead optimization via simultaneous virtual library searches and structure-based rational design efforts led to potent antagonists of thrombin-induced activation. Interestingly, this series of antagonists was active against PAR4 activation by the native protease thrombin cleavage but not the synthetic PAR4 agonist peptide AYPGKF. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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