Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor

Journal of Medicinal Chemistry
Jinha YuKenneth A Jacobson

Abstract

The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1 H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478).

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Citations

Feb 11, 2020·British Journal of Pharmacology·Kenneth A JacobsonChrista E Müller
Aug 18, 2020·ChemMedChem·Veronica Salmaso, Kenneth A Jacobson
Feb 19, 2021·Frontiers in Oncology·Victor M Matias-BarriosXuesen Dong
Dec 15, 2020·Biochemical Pharmacology·Ivar von Kügelgen
Jun 29, 2021·Frontiers in Molecular Biosciences·Jas KalayanRichard H Henchman
Jul 20, 2021·Future Medicinal Chemistry·Yuyang Wang, Yongtao Duan
Aug 14, 2020·Journal of Medicinal Chemistry·Young-Hwan JungKenneth A Jacobson
Jun 20, 2020·ACS Medicinal Chemistry Letters·Fatma MuftiDaniela Salvemini

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