How Ligands Illuminate GPCR Molecular Pharmacology
Open accessAbstract
G protein-coupled receptors (GPCRs), which are modulated by a variety of endogenous and synthetic ligands, represent the largest family of druggable targets in the human genome. Recent structural and molecular studies have both transformed and expanded classical concepts of receptor pharmacology and have begun to illuminate the distinct mechanisms by which structurally, chemically, and functionally diverse ligands modulate GPCR function. These molecular insights into ligand engagement and action have enabled new computational methods and accelerated the discovery of novel ligands and tool compounds, especially for understudied and orphan GPCRs. These advances promise to streamline the development of GPCR-targeted medications.
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Slightly more than half of non-olfactory GPCRs have annotated drugs and small molecules targeting them.
“Slightly more than half of the non-olfactory GPCRs have annotated drugs and small molecules targeting them53,54,61; see also TABLE 1.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
The Introduction section on understudied and orphan GPCRs describes GPCR-targeted drugs and annotated small-molecule interactors. It does not give a count or proportion of non-olfactory GPCRs with such annotations, so it does not support the claim that the proportion is slightly more than half. (LLM, conf=0.76)
Experimental — accuracy not yet measuredA handful of GPCRs, mainly biogenic amine, muscarinic and opioid receptors, are the most abundantly targeted receptors for FDA-approved medications.
“A recent analysis indicates, however, that a handful of GPCRs — mainly biogenic amine, muscarinic and opioid receptors — represent the most abundantly targeted receptors for FDA-approved medications53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
Alterations in GPCR signalling are implicated in the pathogenesis and treatment of many disorders, including neuropsychiatric, immunological, gastrointestinal, cardiac, renal, hormonal and infectious disorders.
“Alterations in GPCR signalling are implicated in the pathogenesis and treatment of neuropsychiatric55, immunological56, gastrointestinal57,58, cardiac59, renal, hormonal, infectious60 and many other disorders53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
GPCRs are the largest family of druggable targets in the human genome, with 20-30% of approved drugs acting on them.
“GPCRs represent the largest family of druggable targets in the human genome9, with between 20% and 30% of approved drugs acting on them53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
GPCRs are membrane-bound cell-surface receptors that transduce signals via heterotrimeric G proteins, arrestins and other cellular transducers.
“GPCRs are membrane-bound, cell-surface receptors that transduce signals via interactions with heterotrimeric G proteins, arrestins and other cellular transducers53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [53]
Covalent inhibitors have potentially more durable inhibition at the PPI site, leading to improved pharmacology in vivo.
“For covalent inhibitors, one of their chief advantages is potentially more durable inhibition at the PPI site leading to improved pharmacology in vivo [117, 118].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [118]
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In silico design of novel probes for the atypical opioid receptor MRGPRX2
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Self-citationStructure-based discovery of β 2 -adrenergic receptor ligands
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Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65
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Self-citationMultidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed Proximity Labeling
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Intracellular allosteric antagonism of the CCR9 receptor
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Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells
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Extra-helical binding site of a glucagon receptor antagonist
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Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors
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Self-citationInteraction of G protein coupled receptors and cholesterol
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Pharmacogenomic and Structural Analysis of Constitutive G Protein–Coupled Receptor Activity
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New insights from structural biology into the druggability of G protein-coupled receptors
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Activation mechanism of endothelin ETB receptor by endothelin-1
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Pathway and Mechanism of Drug Binding to G-Protein-Coupled Receptors
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Biased Ligands for Better Cardiovascular Drugs
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Endogenous Allosteric Modulators of G Protein–Coupled Receptors
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The antagonism of acetyl choline by atropine
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Self-citationFluorescent Pirenzepine Derivatives as Potential Bitopic Ligands of the Human M1 Muscarinic Receptor
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NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor
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Self-citationMolecular interaction fingerprint approaches for GPCR drug discovery
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From Heptahelical Bundle to Hits from the Haystack
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1 Rhodopsin Mutations in Congenital Night Blindness
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Opportunities and challenges of the 2016 target landscape
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Molecular Dynamics Simulation for All
Hollingsworth, S. A., & Dror, R. O. (2018) · Neuron · doi:10.1016/j.neuron.2018.08.011 · Cited by 3,313 · see citing works
Trends in GPCR drug discovery: new agents, targets and indications
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G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?
Sriram, K., & Insel, P. A. (2018) · Molecular Pharmacology · doi:10.1124/mol.117.111062 · Cited by 1,258 · see citing works
“Data such as those presented here may allow for more accurate evaluation of interactions and off-target effects of approved drugs with GPCRs (Allen and Roth, 2011; Wacker et al., 2017), as well as providing opportunities for novel repurposing of approved drugs.”
BackgroundFree Fatty Acid Receptors in Health and Disease
Kimura, I., Ichimura, A., Ohue‐Kitano, R., & Igarashi, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00041.2018 · Cited by 1,032 · see citing works
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Mechanisms of signalling and biased agonism in G protein-coupled receptors
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A perspective on multi‐target drug discovery and design for complex diseases
Ramsay, R. R., Popović-Nikolić, M. R., Nikolic, K. M., Uliassi, E., & Bolognesi, M. L. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-017-0181-2 · Cited by 722 · see citing works
“Understanding exactly how ligands induce agonism or antagonism involves complex allosteric effects [92].”
BackgroundPharmacogenomics of GPCR Drug Targets
Hauser, A. S., Chavali, S., Masuho, I., Jahn, L. J., Martemyanov, K. A., Gloriam, D. E. I., & Babu, M. M. (2017) · Cell · doi:10.1016/j.cell.2017.11.033 · Cited by 623 · see citing works
“…sites, effector selectivity sites, receptor stability, and oligomerization (Congreve et al., 2017; Costa-Neto et al., 2016; Flock et al., 2015, 2017; Gahbauer Cell 172 , 41–54, January 11, 2018 43 and Bo¨ckmann, 2016; Katritch et al., 2014; Venkatakrishnan et al., 2013, 2016; Wacker et al., 2017).”
“TRUPATH, an Open-Source Biosensor Platform for Interrogating the GPCR Transducerome”
Olsen, R., DiBerto, J., English, J., Glaudin, A. M., Krumm, B., Slocum, S. T., Che, T., Gavin, A. C., McCorvy, J., Roth, B., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0535-8 · Cited by 536 · see citing works
Self-citationN6-Methyladenine DNA Modification in the Human Genome
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G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery
Zhang, M., Chen, T., Lu, X., Lan, X., Chen, K., & Lu, S. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01803-6 · Cited by 520 · see citing works
“117,118 Despite their relatively mature development, side effects derived from low subtype selectivity and promiscuous signaling remain the major hurdle.”
BackgroundStructure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone
Wang, S., Che, T., Levit, A., Shoichet, B. K., Wacker, D., & Roth, B. L. (2018) · Nature · doi:10.1038/nature25758 · Cited by 487 · see citing works
Self-citationStructure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor
Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.024 · Cited by 481 · see citing works
Self-citationUnexplored therapeutic opportunities in the human genome
Oprea, T. I., Bologa, C. G., Brunak, S., Campbell, A., Gan, G. N., Gaulton, A., Gomez, S. M., Guha, R., Hersey, A., Holmes, J., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.14 · Cited by 378 · see citing works
Self-citationEGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics
Freed, D. M., Bessman, N. J., Kiyatkin, A. B., Salazar-Cavazos, E., Byrne, P. O., Moore, J. O., Valley, C. C., Ferguson, K. M., Leahy, D. J., Lidke, D. S., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.017 · Cited by 387 · see citing works
“…to Specify Signaling Kinetics, Cell (2017), https://doi.org/10.1016/j.cell.2017.09.017 G protein-coupled receptor (GPCR) ligands (Lane et al., 2017; Wacker et al., 2017) and further suggest that kinetic proofreading might play an important role in controlling ligand discrimination and RTK…”
InfluentialImpact of GPCR Structures on Drug Discovery
Congreve, M., de Graaf, C., Swain, N. A., & Tate, C. G. (2020) · Cell · doi:10.1016/j.cell.2020.03.003 · Cited by 380 · see citing works
Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor
Che, T., Majumdar, S., Zaidi, S. A., Ondachi, P. W., McCorvy, J. D., Wang, S., Mosier, P. D., Uprety, R., Vardy, E., Krumm, B. E., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.011 · Cited by 373 · see citing works
“Accordingly, even small modifications to identical scaffolds can subtly affect a compound’s binding mode and, thereby, its potency and/or efficacy, as observed for other GPCR ligands (Wacker et al., 2017b).”
Self-citationA Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology
Chen, H., Nwe, P.-K., Yang, Y., Rosen, C. E., Bielecka, A. A., Kuchroo, M. R., Cline, G. W., Kruse, A. C., Ring, A. M., Crawford, J. M., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.036 · Cited by 339 · see citing works
Erratum: Unexplored therapeutic opportunities in the human genome
Oprea, T. I., Bologa, C., Brunak, S., Campbell, A., Gan, G. N., Gaulton, A., Gomez, S. M., Guha, R., Hersey, A., Holmes, J., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.52 · Cited by 304 · see citing works
Self-citationBiased Receptor Signaling in Drug Discovery
Kenakin, T. (2019) · Pharmacological Reviews · doi:10.1124/pr.118.016790 · Cited by 302 · see citing works
“More detailed insights into bias mechanisms have been gained by linking structure-activity relationship (SAR) experiments to receptor structural data (Shukla et al., 2014; Ranjan et al., 2017; Wacker et al., 2017; Zhou et al., 2017; Lee et al., 2018; McCorvy et al., 2018).”
BackgroundGPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures
Shimada, I., Ueda, T., Kofuku, Y., Eddy, M. T., & Kurt Wüthrich, A. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.180 · Cited by 281 · see citing works
Psychedelics as anti-inflammatory agents
Flanagan, T. W., & Nichols, C. D. (2018) · International Review of Psychiatry · doi:10.1080/09540261.2018.1481827 · Cited by 267 · see citing works
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Self-citation5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
Peng, Y., McCorvy, J. D., Harpsøe, K., Lansu, K., Yuan, S., Popov, P. A., Qu, L., Pu, M., Che, T., Nikolajsen, L. F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.001 · Cited by 254 · see citing works
“Structure-guided approaches, perforce, require high-resolution crystal structures in order to exploit ligand-binding pocket interactions at the targeted GPCR (Wacker et al., 2017a; Wang et al., 2017).”
InfluentialSelf-citationMorphine‐induced respiratory depression is independent of β‐arrestin2 signalling
Kliewer, A., Gillis, A., Hill, R., Schmiedel, F., Bailey, C. P., Kelly, E., Henderson, G., Christie, M. J., & Schulz, S. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15004 · Cited by 249 · see citing works
An ALOX12–12-HETE–GPR31 signaling axis is a key mediator of hepatic ischemia–reperfusion injury
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Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential
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Community guidelines for GPCR ligand bias: IUPHAR review 32
Kolb, P., Kenakin, T., Alexander, S. P. H., Bermudez, M., Bohn, L. M., Breinholt, C. S., Bouvier, M., Hill, S. J., Kostenis, E., Martemyanov, K. A., et al. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15811 · Cited by 232 · see citing works
“They recognize a vast diversity of signals ranging from photons, tastants and odours to ions, neurotransmitters, hormones, and cytokines (Harding et al., 2021; Wacker, Stevens, & Roth, 2017).”
Emerging principles of cytokine pharmacology and therapeutics
Saxton, R. A., Glassman, C. R., & García, K. C. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00557-6 · Cited by 223 · see citing works
Intestinal Barrier and Permeability in Health, Obesity and NAFLD
Portincasa, P., Bonfrate, L., Khalil, M., Angelis, M. D., Calabrese, F. M., D’Amato, M., Wang, D. Q. ‐., & Ciaula, A. D. (2021) · Biomedicines · doi:10.3390/biomedicines10010083 · Cited by 212 · see citing works
“Key targets of microbial metabolites are the G protein-coupled receptors (GPCRs) [507] which appear in many cell types and have immune and metabolic functions [508,509].”
BackgroundThe promises and perils of psychedelic pharmacology for psychiatry
McClure‐Begley, T. D., & Roth, B. L. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00421-7 · Cited by 198 · see citing works
“Figure adapted with permission from ref.(132), Elsevier.”
Self-citationStructural Basis for G Protein-Coupled Receptor Activation
Manglik, A., & Kruse, A. C. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00747 · Cited by 195 · see citing works
Wu, V. H., Yeerna, H., Nohata, N., Chiou, J., Harismendy, O., Raimondi, F., Inoue, A., Russell, R. B., Tamayo, P., & Gutkind, J. S. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.005601 · Cited by 176 · see citing works
“The endogenous ligands of more than 140 of these receptors remain unidentified and/or poorly understood, thus, their natural function is currently largely unknown (106).”
BackgroundMaking Sense of Pharmacology: Inverse Agonism and Functional Selectivity
Berg, K. A., & Clarke, W. P. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy071 · Cited by 179 · see citing works
Mechanisms of adhesion G protein–coupled receptor activation
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New concepts in opioid analgesia
Stein, C. (2018) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1516204 · Cited by 175 · see citing works
“A number of bivalent ligands incorporating distinct pharmacophores for two receptors are being investigated [23,101].”
BackgroundInfluentialStructural determinants of 5-HT2B receptor activation and biased agonism
McCorvy, J. D., Wacker, D., Wang, S., Agegnehu, B., Liu, J., Lansu, K., Tribo, A. R., Olsen, R. H. J., Che, T., Jin, J. J., et al. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0116-7 · Cited by 174 · see citing works
Self-citationStructure-inspired design of β-arrestin-biased ligands for aminergic GPCRs
McCorvy, J. D., Butler, K. V., Kelly, B., Rechsteiner, K., Karpiak, J. D., Betz, R. M., Kormos, B. L., Shoichet, B. K., Dror, R. O., Jin, J. J., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2527 · Cited by 170 · see citing works
“Aminergic GPCRs, including histamine, adrenergic, dopamine, serotonin, and muscarinic receptors, are of particular importance to drug discovery as they are targeted by one quarter of currently approved drugs 2, 3 .”
InfluentialSelf-citationG protein-coupled receptors in neurodegenerative diseases and psychiatric disorders
Wong, T., Li, G., Li, S., Gao, W., Chen, G., Gan, S., Zhang, M., Li, H., Wu, S., & Du, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01427-2 · Cited by 168 · see citing works
“), natural products, and pharmacological ligands.(24) A plethora of GPCR signaling events are involved in developing neuropsychiatric disorders.”
BackgroundAllosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts
Wold, E. A., Chen, J., Cunningham, K. A., & Zhou, J. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00875 · Cited by 158 · see citing works
Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions
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“Discovery of ligands that modulate a target’s activity has contributed largely to the understanding of both physiological and pathological processes (Wacker et al., 2017a).”
BackgroundInfluentialNanobody-enabled monitoring of kappa opioid receptor states
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Self-citationMechanism of β 2 AR regulation by an intracellular positive allosteric modulator
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Structural Basis for G Protein–Coupled Receptor Signaling
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Self-citationMolecular basis of opioid receptor signaling
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Self-citationHaloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands
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“51 Although some large-scale efforts have been undertaken, such as for Platynereis and human peptide GPCRs, 29,52,53 most deorphanization studies have focused on single receptors or a subset of GPCR candidates, which may overlook complex interactions of peptides with multiple receptors.”
Engineering cell sensing and responses using a GPCR-coupled CRISPR-Cas system
Kipniss, N. H., Dingal, P. C. D. P., Abbott, T. R., Gao, Y., Wang, H., Dominguez, A. A., Labanieh, L., & Qi, L. S. (2017) · Nature Communications · doi:10.1038/s41467-017-02075-1 · Cited by 113 · see citing works
Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications
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“In silico perturbations can be implied to study the biomolecular system, such as removal of bound ligand from the reported experimental structure and then study its effect on protein conformation [11,12].”
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Fungal G-protein-coupled receptors: mediators of pathogenesis and targets for disease control
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NanoBRET Approaches to Study Ligand Binding to GPCRs and RTKs
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Physicochemical Insights on Terahertz Wave Diminished Side Effects of Drugs from Slow Dissociation
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Structural and Biophysical Mechanisms of Class C G Protein-Coupled Receptor Function
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“This conformational heterogeneity underlies the range of signaling dynamics initiated or inhibited by the many types of orthosteric and allosteric ligands that exist for GPCRs [13].”
BackgroundVEGAS as a Platform for Facile Directed Evolution in Mammalian Cells
English, J. G., Olsen, R. H. J., Lansu, K., Patel, M., White, K., Cockrell, A. S., Singh, D., Strachan, R. T., Wacker, D., & Roth, B. L. (2019) · Cell · doi:10.1016/j.cell.2019.05.051 · Cited by 98 · see citing works
“GPCRs comprise one of the largest protein families in the human genome with >900 unique protein coding genes (Fredriksson et al., 2003; Wacker et al., 2017a).”
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Gut Dysfunction and Non-alcoholic Fatty Liver Disease
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“This is potentially of major biological relevance as GPCRs are expressed by many cell types throughout the body and exert mainly immune and metabolic functions (50, 51).”
BackgroundThe design and development of covalent protein-protein interaction inhibitors for cancer treatment
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Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies
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Targeting Nuclear Receptors with PROTAC degraders
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Optogenetic and chemogenetic therapies for epilepsy
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“If expressed at high levels, only a small fraction of the receptors need to be activated to have a maximal down-stream effect (the so-called ‘receptor reserve’ phenomenon) (Wacker et al., 2017).”
Molecular basis for selective activation of DREADD-based chemogenetics
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Self-citationApplications of Molecular Dynamics Simulations in Drug Discovery
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“Such allosteric modulators can also serve as valuable reagents in the research laboratory, where, by means of their cooperative interactions with orthosteric ligands, they can help to freeze or lock specific receptor conformations so that they can be studied by biophysical techniques (Christopoulos, 2014; Wacker et al…”
BackgroundInfluentialRational design of allosteric modulators: Challenges and successes
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“G protein-coupled receptors (GPCRs), the largest family of membrane receptors in eukaryotes and the largest class of drug targets (Lagerstrom and Schioth, 2008; Wacker et al., 2017), are particularly well-suited to tethered photopharmacology.”
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“GPCRs with increased expression may thus be functional in cancer cells and activated by endogenous agonists or have constitutive activity that regulates signaling via heterotrimeric G proteins and/or β-arrestin [4].”
BackgroundBiased Signaling of the Mu Opioid Receptor Revealed in Native Neurons
Ehrlich, A. T., Semache, M., Gross, F., Fonte, D. F. D., Runtz, L., Colley, C., Mezni, A., Gouill, C. L., Lukasheva, V., Hogue, M., et al. (2019) · iScience · doi:10.1016/j.isci.2019.03.011 · Cited by 81 · see citing works
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“Given the adverse consequences of “off-target” effects, subtype-specific ligands for receptors have been developed as an alternative approach for improving drug selectivity.(14) For example, the drug siponimod was globally approved in March 2019 for treating adults with relapsing MS by targeting S1PR1 and S1PR5.”
BackgroundChemical Diversity in the G Protein-Coupled Receptor Superfamily
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“The function of GPCRs can be modulated by a plethora of chemical compounds, ranging from large proteins and peptides to small molecule ligands with a variety of physiochemical properties [4].”
Self-citationNature-Derived Peptides: A Growing Niche for GPCR Ligand Discovery
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“The extracellular ligand binding pocket represents the input side; the helical bundles of the hydrophobic core allow for translating the conformational change induced by ligand binding to the output side on the intracellular face: this results in both G protein-dependent and G protein-independent cellular signals [4,6…”
BackgroundStructural perspective of class B1 GPCR signaling
Cong, Z., Liang, Y.-L., Zhou, Q., Darbalaei, S., Zhao, F., Feng, W., Zhao, L., Xu, H. E., Yang, D., & Wang, M. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.01.002 · Cited by 80 · see citing works
The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications
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“For studies utilizing native GLP-1, some of the biological activities observed may reflect generation of GLP-1(9-36) and GLP-1(28-36).”
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Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2
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Quantum effects in the brain: A review
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Structural basis for signal recognition and transduction by platelet-activating-factor receptor
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Self-citationCovalent‐Allosteric Inhibitors to Achieve Akt Isoform‐Selectivity
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Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator
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Self-citationIncreasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry
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Josts, I., Nitsche, J., Maric, S., Mertens, H. D. T., Moulin, M., Haertlein, M., Prévost, S. F., Svergun, D. I., Büsch, S., Forsyth, V. T., et al. (2018) · Structure · doi:10.1016/j.str.2018.05.007 · Cited by 70 · see citing works
Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases
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Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs
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Self-citationNeuromodulation for the Treatment of Epilepsy: A Review of Current Approaches and Future Directions
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“420 This mechanism is reminiscent of the “biased agonism” paradigm that is well421 established for G-protein-coupled receptors (GPCRs), where multiple ligands of the 422 same receptor can preferentially activate different downstream signaling pathways by 423 inducing distinct activation kinetics or conformations of th…”
Background100 years of modelling ligand–receptor binding and response: A focus on GPCRs
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“GPCRs may be activated by stimuli as diverse as photons, organic odorants, nucleotides/nucleosides, peptides, larger proteins and a plethora of small molecules such as hormones, lipids and neurotransmitters.”
BackgroundInfluentialTargeting the PAC1 Receptor for Neurological and Metabolic Disorders
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Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features
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Targeting GPCR Signaling for Idiopathic Pulmonary Fibrosis Therapies
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“The number of drugs which target GPCRs is very large; however the number of distinct GPCRs targeted by those drugs is actually only a small percentage of the more than 800 unique GPCRs [101].”
BackgroundStructure, dynamics and lipid interactions of serotonin receptors: excitements and challenges
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“Interestingly, closely bound cholesterol molecules have been reported in crystal structures of the serotonin2A and serotonin2B receptors (Liu et al. 2013; Wacker et al. 2013; Wacker et al. 2017a; McCorvy et al. 2018; Kimura et al. 2019; Kim et al. 2020; see Fig.”
BackgroundInfluentialApplications of machine learning in GPCR bioactive ligand discovery
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How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs
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Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor
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“6, A and B), suggesting that CaSR may exhibit a superactive state induced by a positive allosteric modulator or intracellular inducers (45, 57).”
Background
- Authors
- Wacker, D., Stevens, R. C., & Roth, B. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Southern California (US)
- Corresponding author
- Roth, Bryan L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 170
- Issue
- 3
- Pages
- 414-427
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5560499
- OpenAlex
- W2741191097
- Cited by
- 560
- References
- 115
- Citations by year
- 2026: 33 · 2025: 46 · 2024: 56 · 2023: 51 · 2022: 68 · 2021: 75 · 2020: 73 · 2019: 75 · 2018: 70 · 2017: 12
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Health (RO1MH112205, UO1MH104974, U19MH82441, PO1DA035764)
- Michael Hooker Distinguished Professorship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- G protein-coupled receptors, GPCR pharmacology, ligand binding, ligand-receptor interactions, orphan G protein-coupled receptor, tool compounds, computational drug discovery, GPCR structure
- MeSH terms
- Animals, Humans, Ligands, Models, Molecular, Signal Transduction, Receptors, G-Protein-Coupled, Drug Discovery, Molecular Targeted Therapy
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