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Virtual screening leads to the discovery of novel non-nucleotide P2Y? receptor antagonists.

ABSTRACT: The P2Y(1) receptor (P2Y(1)R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y(1)R ligands and the putative shape and size of the receptor binding pocket, we have identified novel antagonist hits of ?M affinity derived from a N,N'-bis-arylurea chemotype. Unlike the vast majority of known P2Y(1)R antagonists, these drug-like compounds do not have a nucleotidic scaffold or highly negatively charged phosphate groups. Hence, our compounds may provide a direction for the development of receptor probes with altered physicochemical properties.

SUBMITTER: Costanzi S

PROVIDER: S-EPMC3420346 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Virtual screening leads to the discovery of novel non-nucleotide P2Y₁ receptor antagonists.

Costanzi Stefano S Santhosh Kumar T T Balasubramanian Ramachandran R Kendall Harden T T Jacobson Kenneth A KA

Bioorganic & medicinal chemistry 20120703 17

The P2Y(1) receptor (P2Y(1)R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y(1)R ligands and the putative shape and size of the receptor binding pocket, we have identified ...[more]

PMID: 22831801

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