Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search

Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search

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...

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Main Authors: Takeshi Hiramoto, Yosuke Nonaka, Kazuko Inoue, Takefumi Yamamoto, Mariko Omatsu-Kanbe, Hiroshi Matsuura, Keigo Gohda, Norihisa Fujita
Format: Article
Language:English
Published: Elsevier 2004-01-01
Series:Journal of Pharmacological Sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S1347861319324600
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spelling doaj-8528c68d9d494f85b4c708ca72a782f52020-11-24T21:58:31ZengElsevierJournal of Pharmacological Sciences1347-86132004-01-019518193Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico SearchTakeshi Hiramoto0Yosuke Nonaka1Kazuko Inoue2Takefumi Yamamoto3Mariko Omatsu-Kanbe4Hiroshi Matsuura5Keigo Gohda6Norihisa Fujita7Laboratory of Pharmcoinformatics, Department of Bioscience and Biotechnology, College of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, JapanLaboratory of Pharmcoinformatics, Department of Bioscience and Biotechnology, College of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, JapanLaboratory of Pharmcoinformatics, Department of Bioscience and Biotechnology, College of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, JapanCentral Research Laboratory, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, JapanDepartment of Physiology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, JapanDepartment of Physiology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, JapanCAMM-Kansai, Higashinada, Kobe 658-0046, JapanLaboratory of Pharmcoinformatics, Department of Bioscience and Biotechnology, College of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan; Corresponding author. FAX: +81-77-561-5203 E-mail: nori@is.ritsumei.ac.jpG 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:: G protein-coupled receptor, P2Y1 receptor, in silico screening, AutoDock, 5-phosphoribosyl-1-pyrophosphatehttp://www.sciencedirect.com/science/article/pii/S1347861319324600
collection DOAJ
language English
format Article
sources DOAJ
author Takeshi Hiramoto
Yosuke Nonaka
Kazuko Inoue
Takefumi Yamamoto
Mariko Omatsu-Kanbe
Hiroshi Matsuura
Keigo Gohda
Norihisa Fujita
spellingShingle Takeshi Hiramoto
Yosuke Nonaka
Kazuko Inoue
Takefumi Yamamoto
Mariko Omatsu-Kanbe
Hiroshi Matsuura
Keigo Gohda
Norihisa Fujita
Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
Journal of Pharmacological Sciences
author_facet Takeshi Hiramoto
Yosuke Nonaka
Kazuko Inoue
Takefumi Yamamoto
Mariko Omatsu-Kanbe
Hiroshi Matsuura
Keigo Gohda
Norihisa Fujita
author_sort Takeshi Hiramoto
title Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
title_short Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
title_full Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
title_fullStr Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
title_full_unstemmed Identification of Endogenous Surrogate Ligands for Human P2Y Receptors Through an In Silico Search
title_sort identification of endogenous surrogate ligands for human p2y receptors through an in silico search
publisher Elsevier
series Journal of Pharmacological Sciences
issn 1347-8613
publishDate 2004-01-01
description 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:: G protein-coupled receptor, P2Y1 receptor, in silico screening, AutoDock, 5-phosphoribosyl-1-pyrophosphate
url http://www.sciencedirect.com/science/article/pii/S1347861319324600
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