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Chemogenomics approaches for receptor deorphanization and extensions of the chemogenomics concept to phenotypic space

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Author: Horst, E. van der · Peironcely, J.E. · Westen, G.J.P. van · Hoven, O.O. van den · Galloway, W.R.J.D. · Spring, D.R. · Wegner, J.K. · Vlijmen, H.W.T. van · Ijzerman, A.P. · Overington, J.P. · Bender, A.
Type:article
Date:2011
Source:Current Topics in Medicinal Chemistry, 15, 11, 1964-1977
Identifier: 434667
doi: doi:10.2174/156802611796391230
Keywords: Nutrition · Chemogenomics · Deorphanization · G-protein coupled receptors · GPCR · Mode of action analysis · Orphan receptors · Proteochemometrics · Target prediction · Virtual screening · G protein coupled receptor · ligand · Bayes theorem · chemical genetics · chemistry · chemogenomic · drug activity · drug industry · genomics · phenotype · proteochemometrics · review · Healthy for Life · Healthy Living · Life · QS - Quality & Safety · EELS - Earth, Environmental and Life Sciences

Abstract

Chemogenomic approaches, which link ligand chemistry to bioactivity against targets (and, by extension, to phenotypes) are becoming more and more important due to the increasing number of bioactivity data available both in proprietary databases as well as in the public domain. In this article we review chemogenomics approaches applied in four different domains: Firstly, due to the relationship between protein targets from which an approximate relation between their respective bioactive ligands can be inferred, we investigate the extent to which chemogenomics approaches can be applied to receptor deorphanization. In this case it was found that by using knowledge about active compounds of related proteins, in 93% of all cases enrichment better than random could be obtained. Secondly, we analyze different chemin-formatics analysis methods with respect to their behavior in chemogenomics studies, such as subgraph mining and Baye-sian models. Thirdly, we illustrate how chemogenomics, in its particular flavor of 'proteochemometrics', can be applied to extrapolate bioactivity predictions from given data points to related targets. Finally, we extend the concept of 'chemoge-nomics' approaches, relating ligand chemistry to bioactivity against related targets, into phenotypic space which then falls into the area of 'chemical genomics' and 'chemical genetics'; given that this is very often the desired endpoint of approaches in not only the pharmaceutical industry, but also in academic probe discovery, this is often the endpoint the experimental scientist is most interested in. © 2011 Bentham Science Publishers.