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

15 Citations (Scopus)

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 2004
Externally publishedYes

Fingerprint

G-Protein-Coupled Receptors
Purinergic P2Y1 Receptors
Computer Simulation
Ligands
Purinergic P2X2 Receptors
Phosphoribosyl Pyrophosphate
Purinergic P2Y2 Receptors
Rhodopsin
CHO Cells
Human Body

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search. / Hiramoto, Takeshi; Nonaka, Yosuke; Inoue, Kazuko; Yamamoto, Takefumi; Omatsu-Kanbe, Mariko; Matsuura, Hiroshi; Gohda, Keigo; Fujita, Norihisa.

In: Journal of Pharmacological Sciences, Vol. 95, No. 1, 05.2004, p. 81-93.

Research output: Contribution to journalArticle

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, vol. 95, no. 1, pp. 81-93. https://doi.org/10.1254/jphs.95.81
Hiramoto, Takeshi ; Nonaka, Yosuke ; Inoue, Kazuko ; Yamamoto, Takefumi ; Omatsu-Kanbe, Mariko ; Matsuura, Hiroshi ; Gohda, Keigo ; Fujita, Norihisa. / Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search. In: Journal of Pharmacological Sciences. 2004 ; Vol. 95, No. 1. pp. 81-93.
@article{95c708458d754133b4e4b3dbb8496e10,
title = "Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search",
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.",
keywords = "5-phosphoribosyl-1-pyrophosphate, AutoDock, G protein-coupled receptor, In silico screening, P2Y receptor",
author = "Takeshi Hiramoto and Yosuke Nonaka and Kazuko Inoue and Takefumi Yamamoto and Mariko Omatsu-Kanbe and Hiroshi Matsuura and Keigo Gohda and Norihisa Fujita",
year = "2004",
month = "5",
doi = "10.1254/jphs.95.81",
language = "English (US)",
volume = "95",
pages = "81--93",
journal = "Journal of Pharmacological Sciences",
issn = "1347-8613",
publisher = "Japanese Pharmacological Society",
number = "1",

}

TY - JOUR

T1 - Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search

AU - Hiramoto, Takeshi

AU - Nonaka, Yosuke

AU - Inoue, Kazuko

AU - Yamamoto, Takefumi

AU - Omatsu-Kanbe, Mariko

AU - Matsuura, Hiroshi

AU - Gohda, Keigo

AU - Fujita, Norihisa

PY - 2004/5

Y1 - 2004/5

N2 - 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.

AB - 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.

KW - 5-phosphoribosyl-1-pyrophosphate

KW - AutoDock

KW - G protein-coupled receptor

KW - In silico screening

KW - P2Y receptor

UR - http://www.scopus.com/inward/record.url?scp=3042829023&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042829023&partnerID=8YFLogxK

U2 - 10.1254/jphs.95.81

DO - 10.1254/jphs.95.81

M3 - Article

VL - 95

SP - 81

EP - 93

JO - Journal of Pharmacological Sciences

JF - Journal of Pharmacological Sciences

SN - 1347-8613

IS - 1

ER -