A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

BMC Bioinformatics

Research Article

Yasushi Okuno¹  Julio E Peironcely²  Margot W Beukers²  Herman WT van Vlijmen²  Eelke van der Horst²  Jonathan R Lane²  Adriaan P IJzerman²  Andreas Bender³  Michael TM Emmerich⁴ 

[1] Department of PharmacoInformatics, Center for Integrative Education of Pharmacy Frontier, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333CC, The Netherlands;Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333CC, The Netherlands;Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK;Leiden Institute for Advanced Computer Science, University of Leiden, The Netherlands;

关键词: Sequence Space;    Adenosine Receptor;    P2Y1 Receptor;    Orphan Receptor;    Prostanoid Receptor;   

DOI  :  10.1186/1471-2105-11-316

 received in 2010-03-04, accepted in 2010-06-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundG protein-coupled receptors (GPCRs) represent a family of well-characterized drug targets with significant therapeutic value. Phylogenetic classifications may help to understand the characteristics of individual GPCRs and their subtypes. Previous phylogenetic classifications were all based on the sequences of receptors, adding only minor information about the ligand binding properties of the receptors. In this work, we compare a sequence-based classification of receptors to a ligand-based classification of the same group of receptors, and evaluate the potential to use sequence relatedness as a predictor for ligand interactions thus aiding the quest for ligands of orphan receptors.ResultsWe present a classification of GPCRs that is purely based on their ligands, complementing sequence-based phylogenetic classifications of these receptors. Targets were hierarchically classified into phylogenetic trees, for both sequence space and ligand (substructure) space. The overall organization of the sequence-based tree and substructure-based tree was similar; in particular, the adenosine receptors cluster together as well as most peptide receptor subtypes (e.g. opioid, somatostatin) and adrenoceptor subtypes. In ligand space, the prostanoid and cannabinoid receptors are more distant from the other targets, whereas the tachykinin receptors, the oxytocin receptor, and serotonin receptors are closer to the other targets, which is indicative for ligand promiscuity. In 93% of the receptors studied, de-orphanization of a simulated orphan receptor using the ligands of related receptors performed better than random (AUC > 0.5) and for 35% of receptors de-orphanization performance was good (AUC > 0.7).ConclusionsWe constructed a phylogenetic classification of GPCRs that is solely based on the ligands of these receptors. The similarities and differences with traditional sequence-based classifications were investigated: our ligand-based classification uncovers relationships among GPCRs that are not apparent from the sequence-based classification. This will shed light on potential cross-reactivity of GPCR ligands and will aid the design of new ligands with the desired activity profiles. In addition, we linked the ligand-based classification with a ligand-focused sequence-based classification described in literature and proved the potential of this method for de-orphanization of GPCRs.

【 授权许可】

Unknown   
© van der Horst et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.