Virtual Screening Leads to the Discovery of Novel Non-nucleotide P2Y₁ Receptor Antagonists

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2012 Jul 27

PMID 22831801

Citations 7

Authors

Stefano Costanzi

T Santhosh Kumar

Ramachandran Balasubramanian

T Kendall Harden

Kenneth A Jacobson

Affiliations

Soon will be listed here.

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 μM 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.

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