Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search

Takeshi Hiramoto, Yosuke Nonaka, Kazuko Inoue, Takefumi Yamamoto, Mariko Omatsu-Kanbe, Hiroshi Matsuura, Keigo Gohda, Norihisa Fujita

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

G protein-coupled receptors (GPCRs) are distributed widely throughout the human body, and nearly 50% of current medicines act on a GPCR. GPCRs are considered to consist of seven transmembrane α-helices that form an α-helical bundle in which agonists and antagonists bind. A 3D structure of the target GPCR is indispensable for designing novel medicines acting on a GPCR. We have previously constructed the 3D structure of human P2Y1 (hP2Y1) receptor, a GPCR, by homology modeling with the 3D structure of bovine rhodopsin as a template. In the present study, we have employed an in silico screening for compounds that could bind to the hP2Y1-receptor model using AutoDock 3.0. We selected 21 of the 30 top-ranked compounds, and by measuring intracellular Ca2+ concentration, we identified 12 compounds that activated or blocked the hP2Y1 receptor stably expressed in recombinant CHO cells. 5-Phosphoribosyl-1-pyrophosphate (PRPP) was found to activate the hP2Y1 receptor with a low ED50 value of 15 nM. The Ca2+ assays showed it had no significant effect on P2Y2, P2Y6, or P2X2 receptors, but acted as a weak agonist on the P2Y12 receptor. This is the first study to rationally identify surrogate ligands for the P2Y-receptor family.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalJournal of Pharmacological Sciences
Volume95
Issue number1
DOIs
StatePublished - May 1 2004

Keywords

  • 5-phosphoribosyl-1-pyrophosphate
  • AutoDock
  • G protein-coupled receptor
  • In silico screening
  • P2Y receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Hiramoto, T., Nonaka, Y., Inoue, K., Yamamoto, T., Omatsu-Kanbe, M., Matsuura, H., Gohda, K., & Fujita, N. (2004). Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search. Journal of Pharmacological Sciences, 95(1), 81-93. https://doi.org/10.1254/jphs.95.81