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Papers of the Week

Papers: 12 Mar 2022 - 18 Mar 2022

Pharmacology/Drug Development

2022 Mar 14

J Chem Inf Model

Discovery of P2Y Receptor Antagonist Scaffolds through Virtual High-Throughput Screening.


Neumann A, Attah I, Al-Hroub H, Namasivayam V, Müller CE
J Chem Inf Model. 2022 Mar 14.
PMID: 35285230.


The human ATP- and UTP-activated P2Y receptor (P2YR) is a G protein-coupled receptor involved in several pathophysiological conditions including acute and chronic inflammation, cancer, and pain. Despite its potential as a novel drug target, only few P2YR antagonists have been developed so far, all of which suffer from severe drawbacks. These include (i) high polarity due to one or several negative charges resulting in low oral bioavailability, (ii) metabolic instability and generally poor pharmacokinetic properties, and/or (iii) lack of selectivity, which limits their utility for and studies aimed at target validation. In search of new druglike scaffolds for P2YR antagonists, we employed a structure-based virtual high-throughput screening approach utilizing the complex of a P2YR homology model with one of the most potent and selective orthosteric antagonists described so far, AR-C118925 (). After virtual screening of 3.2 million molecules, 58 compounds were purchased and pharmacologically evaluated. Several novel antagonist scaffolds were discovered, and their binding modes at the human P2YR were analyzed by molecular docking studies. The investigated antagonists likely share a similar binding mode with which includes accommodation of bulky, lipophilic groups in the putative orthosteric binding site of the P2YR. The discovered scaffolds and the elucidated structure-activity relationships provide a basis for the development of future drug candidates for the P2YR which have great potential as novel drugs.