International Journal of Molecular Sciences Review Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors Antonella Di Pizio * , Maik Behrens and Dietmar Krautwurst Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Freising, 85354, Germany; [email protected] (M.B.); [email protected] (D.K.) * Correspondence: [email protected]; Tel.: +49-8161-71-2904; Fax: +49-8161-71-2970 Received: 13 February 2019; Accepted: 12 March 2019; Published: 20 March 2019 Abstract: G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules. Keywords: smell; taste; flavour molecules; drugs; chemosensory receptors; ecnomotopic expression 1. Introduction Thirty-five percent of approved drugs act by modulating G protein-coupled receptors (GPCRs) [1,2]. GPCRs, also named 7-transmembrane (7TM) receptors, based on their canonical structure, are the largest family of membrane receptors in the human genome. The most commonly-used classification system divides GPCRs into six classes: class A (rhodopsin-like), consisting of over 80% of all GPCRs, class B (secretin-like), class C (metabotropic glutamate receptors), class D (pheromone receptors), class E (cAMP receptors) and class F (frizzled/smoothened family) [3–5]. The high GPCRs’ “druggability”, that is, the likelihood of modulating a target by small-molecule drugs [6], is due to a combination of numerous factors, including their physiological and pathological relevance, their expression in the plasma membrane, which facilitates molecular interactions in the extracellular milieu, and a very defined binding site [2,7–9]. The number of GPCRs targeted by drugs is currently 134, ~16% of the ~800 GPCRs in the human genome [1]. Remaining 84% of the GPCR repertoire include orphan GPCRs (~100 receptors) and sensory GPCRs (olfactory, taste and visual receptors). Chemosensory GPCRs (csGPCRs) constitute structurally and phylogenetically diverse subgroups within the superfamily of GPCRs (Figure1). Int. J. Mol. Sci. 2019, 20, 1402; doi:10.3390/ijms20061402 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x 1402 2 of 2122 Figure 1. Architecture of csGPCRs. (A) Chemosensory receptors classified as class A G protein-coupled receptorsFigure 1. (GPCRs),Architecture whose of orthostericcsGPCRs. ( bindingA) Chemosensory site is located receptors inside theclassified TM domain, as class i.e., A ORs, G protein TAARs- andcoupled TAS2Rs. receptors (B) Chemosensory (GPCRs), whose receptors orthosteric classified binding as class site Cis GPCRs,located inside whose the orthosteric TM domain, binding i.e., site ORs, is locatedTAARs inand the TAS2Rs. Venus flytrap (B) Chemosensory (VFT) domain, receptors i.e., TAS1R2/TAS1R3 classified as andclass TAS1R1/TAS1R3. C GPCRs, whose orthosteric binding site is located in the Venus flytrap (VFT) domain, i.e., TAS1R2/TAS1R3 and TAS1R1/TAS1R3. Odorant receptors (ORs) are class A GPCRs, encoded by ~400 genes in human and thus representOdorant the receptors largest GPCR (ORs) subgroup. are class A Additional GPCRs, encoded class A by csGPCRs ~400 genes in thein human nasal cavity and thus are represent the trace amine-associatedthe largest GPCR receptors subgroup. (TAARs). Additional Six functional class A csGPCRsTAAR genes in th havee nasal been cavity found are in human the trace and amine except- forassociated TAAR1, receptors all receptor (TAARs). subtypes Six arefunctional suggested TAAR to begenes targeted have bybeen odorants, found in particularly human and by except volatile for aminesTAAR1, [ 10all– 12receptor]. subtypes are suggested to be targeted by odorants, particularly by volatile aminesBitter [10– taste12]. signalling is initiated by 25 TAS2Rs [13–15], classified as class A GPCRs for their architectureBitter taste and signalling binding site is locationinitiated [16by]. 25 By TAS2Rs contrast, [13 there–15], are classified only three as class class CA GPCRs,GPCRs for TAS1R1, their TAS1R2architecture and and TAS1R3, binding which site form location functional [16]. By heterodimers contrast, there that are specifically only three recognize class C GPCRs, sweeteners TAS1R1, and aminoTAS1R2 acids: and TAS1R3, the TAS1R2/TAS1R3 which form functional combination heterodimers recognizes that natural specificall and artificialy recognize sweeteners sweeteners whereas and theamino TAS1R1/TAS1R3 acids: the TAS1R2/TAS1R3 is involved in combination umami taste recognizes [17–20]. GPCRs natural have and been artificial suggested sweeteners to mediate wherea alsos the orosensoryTAS1R1/TAS1R3 perception is involved of fat [ 21in– umami23] and taste kokumi [17– (i.e.,20]. GPCRs enhancement have been of mouthfulness suggested to and mediate thickness also ofthe food orosensory perception) perception substances of [24fat, 25[21]. –23] and kokumi (i.e., enhancement of mouthfulness and thicknessIt is of well-established food perception) that, substances by csGPCRs [24,25]. within our chemical senses smell and taste, we constantlyIt is well monitor-established our external that, by chemical csGPCRs environment within our tochemical detect and senses discriminate smell and especially taste, we constantly foodborne stimulimonitor [ 26our,27 external]. However, chemical canonical environment csGPCRs to detect are also and expressed discriminate in tissues especially not directlyfoodborne related stimuli to the[26,27] detection. However, of odorants canonical or csGPCRs tastants [are28– also31], whichexpressed strongly in tissues suggest not directly their role related in the to monitoring the detection of internalof odorant environments.s or tastants Indeed, [28–31] in, somewhich cases strongly their physiologicalsuggest their roles role and in theirthe monitoring involvement of in internal serious diseases,environments. like respiratory Indeed, in and some metabolic cases their diseases physiological and even cancer, roles haveand their been characterizedinvolvement in [32 serious]. diseases,The factlike thatrespiratory csGPCRs and have metabolic pharmacological diseases and relevance even cancer, and that have they been belong characterized to a highly druggable[32]. proteinThe family, fact that unequivocally csGPCRs pointshave pharmacological them out as new attractiverelevance drugand targets,that they increasing belong theto potentiala highly therapeuticdruggable protein GPCR family, target space unequivocally [33]. Since point previouss them analyses out as new on emergingattractive drugdrug designtargets, trendsincreasing and opportunitiesthe potential therapeutic have focused GPCR onthe target non-sensory space [33] GPCR-ome. Since previous [1,2,34 analyses,35], in thison emerging review we drug attempt design to describetrends and the opportunities state-of-the-art have ofcsGPCR focused researchon the non and-sensory explore GPCR the potential-ome [1,2,34,35] druggability, in this of csGPCRs.review we attempt to describe the state-of-the-art of csGPCR research and explore the potential druggability of 2.csGPCRs. “Ecnomotopic” csGPCRs and Their Modulation by Small Molecules OR gene expression has been established in a multitude of human tissues, that is, brain, blood 2. “Ecnomotopic” csGPCRs and Their Modulation by Small Molecules leukocytes, airway smooth muscle, skin, gut [36–45]. Similarly, TAS1Rs and TAS2Rs are located in tissuesOR other gene than expression the tongue has andbeen palate established epithelium; in a multitude including gastrointestinalof human tissues, tract, that heart, is, brain, leukocytes, blood Int. J. Mol. Sci. 2019, 20, x 3 of 21 vascularleukocytes, smooth airway muscle, smooth airway muscle, epithelium, skin, gut skin, [36– lung45]. Similarly, and brain TAS1Rs [39,46–55 and]. TAS2Rs are located in tissuesTheThe other expression than of ofthe extra-nasal extra-nasal tongue ORs and ORs and palate and extra-oral extra-oral epithelium TAS1Rs TAS1Rs and; including TAS2Rs and TAS2Rs isgastrointestinal frequently is frequently defined tract, as defined heart, as “ectopic”leukocytes,“ectopic” [etymology:[etymology: vascular smooth from Greek, muscle, ἐκ (out) airwayκ(out) + +τ epithelium,óτόποςπoσ(place),(place), skin, out-of-the-placeout-of-the-place lung and ]brain][ [32,56].32,56 [39,46]. Ectopic Ectopic–55] .is is a a medicalFormatted: Not Highlight medical term used for “a biological event or process occurring in an abnormal location or position within the body” [56,57]. However, csGPCRs outside their canonical places cannot be considered Formatted: Not Highlight abnormal and we prefer to use the term “ec-nomotopic” [etymology: from Greek, ἐκ(out) + νόμος(law, custom) + τόπος(place), out-of-the-usual(conventional)-place]. To the best of our knowledge, the