Review
Gene to screenScreening the receptorome: an efficient approach for drug discovery and target validation
Gene to screen
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.
References (74)
- et al.
Mining the receptorome
J. Biol. Chem.
(2005) - et al.
The druggable genome: an update
Drug Discov. Today
(2005) Orphan G-protein-coupled receptors and natural ligand discovery
Trends Pharmacol. Sci.
(2001)SAR of psilocybin analogs: discovery of a selective 5-HT(2C) agonist
Bioorg Med Chem Lett
(2005)Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
Cell
(1999)The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene
Cell
(1999)Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity
Neuron
(2001)A homogeneous high throughput nonradioactive method for measurement of functional activity of Gs-coupled receptors in membranes
J. Biomol. Screen.
(2002)Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery
Pharmacol. Ther.
(2004)Development of KiBank, a database supporting structure-based drug design
Comput. Biol. Chem.
(2004)
Chimeric G proteins allow a high-throughput signaling assay of Gi-coupled receptors
Anal. Biochem.
G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C
J. Biol. Chem.
High-throughput real-time monitoring of Gs-coupled receptor activation in intact cells using cyclic nucleotide-gated channels
Eur. J. Pharmacol.
Multiplicity of mechanisms of serotonin receptor signal transduction
Pharmacol. Ther.
Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes
Neuropsychopharmacology
Agonist-receptor efficacy. II. Agonist trafficking of receptor signals
Trends Pharmacol. Sci.
From magic bullets to designed multiple ligands
Drug Discov. Today
Valvular heart disease in patients taking pergolide
Mayo Clin. Proc.
The US Food and Drug Administration's registry of patients with pergolide-associated valvular heart disease
Mayo Clin. Proc.
Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability
Trends Pharmacol. Sci.
Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression
Neuropharmacology
5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern
Biol. Psychiatry
Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction
Sci. STKE
3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro
Mol. Pharmacol.
In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates
J. Pharmacol. Exp. Ther.
G-protein-coupled receptors at a glance
J. Cell Sci.
Receptorome screening for CNS drug discovery
IDrugs
The emergence of the drug receptor theory
Nat. Rev. Drug Discov.
The druggable genome
Nat. Rev. Drug Discov.
The repertoire of G-protein coupled receptors in fully sequenced genomes
Mol. Pharmacol.
The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints
Mol. Pharmacol.
International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin)
Pharmacol. Rev.
Molecular biology of serotonin receptors structure and function at the molecular level
Curr. Top. Med. Chem.
The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor
Nature
Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia
Nat. Rev. Drug Discov.
The human polyomavirus, JCV, uses serotonin receptors to infect cells
Science
Finding new tricks for old drugs: an efficient route for public-sector drug discovery
Nat. Rev. Drug Discov.
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