Review
Gene to screen
Screening the receptorome: an efficient approach for drug discovery and target validation

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The receptorome, comprising at least 5% of the human genome, encodes receptors that mediate the physiological, pathological and therapeutic responses to a vast number of exogenous and endogenous ligands. Not surprisingly, the majority of approved medications target members of the receptorome. Several in silico and physical screening approaches have been devised to mine the receptorome efficiently for the discovery and validation of molecular targets for therapeutic drug discovery. Receptorome screening has also been used to discover, and thereby avoid, the molecular targets responsible for serious and unforeseen drug side effects.

Introduction

The plasma membrane plays host to more than 20 different families of receptors, including over 1000 different proteins [1], which we have dubbed the ‘receptorome’ 2, 3. The G-protein-coupled receptor (GPCR) superfamily represents the single largest slice of the receptorome [4], although the receptorome also includes toll-like receptors, integrin receptors, low-density lipoprotein receptors, receptor protein tyrosine kinases and phosphatases, cytokine receptors and even some ion channels that can function as receptors (http://receptome.stanford.edu/HPMR) [5] (Figure 1). The receptorome has evolved to ‘capture’ a vast and diverse universe of ligands, such as photons, odorants, tastants, pheromones, viruses, neurotransmitters, amino acids, polypeptides, hormones, nucleotides, ions, intermediary metabolites and catabolites, natural products and lipids [6].

The therapeutic exploitation of the interaction between extracellular ligands and cell surface receptors, which originated as the ‘drug–receptor’ concept, is considered to be one of the great ideas and insights in 20th-century biomedical science [7]. Not surprisingly, this conceptual insight has led to the discovery and development of a large number of drugs that target members of the receptorome. Indeed, because of continuing advances in target identification, screening technologies and target validation, receptorome-based drug discovery efforts are likely to be productive for many decades to come. Not surprisingly, most experts conclude that the receptorome accounts for the largest portion in the ‘druggable genome’, with GPCRs consistently leading the pack 6, 8, 9.

Section snippets

Deorphanizing the receptorome for target discovery and validation: focus on GPCRs

The largest portion of the receptorome comprises the seven transmembrane spanning receptors known as the GPCRs. The GPCR superfamily constitutes more than 50% of the receptorome and 2% of the human genome (Figure 1) and is responsible for mediating multiple cellular responses to a diverse set of endogenous and exogenous ligands, including biogenic amines, amino acids, peptides, lipids, odorants, nucleotides and photons. A recent phylogenetic analysis of the human GPCR superfamily has revealed

Current receptoromics: physical screening approaches for the receptorome

In this section, we summarize available technologies for screening the receptorome in a parallel fashion. Ideally, one would simultaneously screen the entire complement of receptors in the genome with compound libraries to discover compounds with the requisite potency and selectivity to be used as lead compounds for therapeutic drug development [6]. Unfortunately, there is currently no single approach that can be used to perform such massively parallel and unbiased screening because of

Computationally screening the receptorome: facilitating HTS drug discovery using in silico techniques

Computational methods have become a crucial component of many drug discovery programs, from hit identification to lead optimization and beyond, and approaches such as ligand- or structure-based virtual screening techniques are widely used in many discovery efforts [54]. In fact, various computational methods have been applied to facilitate the experimental deorphanization of oGPCRs by identifying potential cognate ligands and putative signaling pathways [52].

One of the most popular

Mining the receptorome for cancer therapeutics: targeting receptor tyrosine kinases

In principle, it should also be possible to screen other members of the receptorome in a parallel fashion for drug discovery and drug development efforts. One target class that has received particular interest is the receptor tyrosine kinase family, which includes many anticancer therapeutic targets, including epidermal growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor receptors and vascular endothelial growth factor receptors [1]. Recently, as part of

Prader–Willi-syndrome, heart valves and obesity: a receptorome success story

Fenfluramine, one of the most widely prescribed appetite suppressants used for long-term management of obesity, was taken off the market in 1997 after it was found to increase the risk of developing pulmonary hypertension and valvular heart disease (VHD) [62]. In a broad-based receptorome screen performed by the National Institute of Mental Health Psychoactive Drug Screening Program, the molecular target responsible for fenfluramine-induced valvular heart disease was identified as being the

Conclusions

Receptorome screening provides an unbiased and highly efficient approach for molecular target discovery and validation. Development of novel screening technologies and improved chemoinformatics resources will greatly enhance our ability to mine the receptorome for therapeutic drug discovery.

Acknowledgements

This work was supported in part by the NIMH Psychoactive Drug Screening Program and by grants RO1MH57635, RO1MH61887, RO1DA01766 and KO2MH01366 to B.L.R.

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