title: Virtual screening leads to the discovery of novel non-nucleotide P2Y₁ 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 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.
authors: Laboratory of Biological Modeling, National Institutes of Health, Bethesda, MD 20892, USA. costanzi@american.edu
authors: Stefano
authors: S
authors: Costanzi
authors: T
authors: T
authors: Santhosh Kumar
authors: Ramachandran
authors: R
authors: Balasubramanian
authors: T
authors: T
authors: Kendall Harden
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D058472:Receptors, Purinergic P2Y1; D013449:Sulfonamides; D000096926:Benzenesulfonamides