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G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 35270

Special Issue Editor

Prof. Dr. Ingebrigt Sylte

E-Mail Website
Guest Editor
Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, Norway
Interests: CNS pharmacology; signal transduction; substrate inhibition and translocation; allosteric mechanisms; in silico and in vitro compound screening

Special Issue Information

Dear Colleagues,

Diseases affecting the CNS are among the most common causes of disease burden in the world, and, in spite of significant breakthroughs, there is still a large need for new drugs. An increasing number of three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) and transporter proteins in the CNS have become available during the recent years. The 3D structures of molecules and molecular complexes transform our understanding of signal transduction and membrane translocation mechanisms and provide insights into the molecular basis of diseases. In addition, the 3D structures of GPCRs and transporter proteins are crucial in the discovery of new CNS drugs. Virtual screening methods combined with experimental verification studies can identify starting hit compounds for drug discovery, while the 3D structures of compounds bound to a protein can guide medicinal chemistry to improve affinity, selectivity, or biological efficacy.

This Special Issue welcomes original articles, reviews, and communications on all aspects of GPCRs and transporters in the CNS, including structural and computational studies, drug design and medicinal chemistry, biochemical and biophysical studies of functional mechanisms and target–ligand interactions in vitro or in living cells.

Prof. Dr. Ingebrigt Sylte
Guest Editor

Manuscript Submission Information

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Keywords

  • 3D structure
  • Homology modelling
  • Molecular dynamics
  • Molelcular mechanims
  • Structure–activity relationships
  • Drug discovery
  • In silico and in vitro screening
  • Biological assays
  • Ortosteric and allosteric compounds
  • Biased agonism
  • Transport inhibitors

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Published Papers (7 papers)

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Research

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16 pages, 40088 KiB  
Article
Effective Use of Empirical Data for Virtual Screening against APJR GPCR Receptor
by Laura C. E. Manoliu, Eliza C. Martin, Adina L. Milac and Laurentiu Spiridon
Molecules 2021, 26(16), 4894; https://doi.org/10.3390/molecules26164894 - 12 Aug 2021
Viewed by 2276
Abstract
Alzheimer’s disease is a neurodegenerative disorder incompatible with normal daily activity, affecting one in nine people. One of its potential targets is the apelin receptor (APJR), a G-protein coupled receptor, which presents considerably high expression levels in the central nervous system. In silico [...] Read more.
Alzheimer’s disease is a neurodegenerative disorder incompatible with normal daily activity, affecting one in nine people. One of its potential targets is the apelin receptor (APJR), a G-protein coupled receptor, which presents considerably high expression levels in the central nervous system. In silico studies of APJR drug-like molecule binding are in small numbers while high throughput screenings (HTS) are already sufficiently many to devise efficient drug design strategies. This presents itself as an opportunity to optimize different steps in future large scale virtual screening endeavours. Here, we ran a first stage docking simulation against a library of 95 known binders and 3829 generated decoys in an effort to improve the rescoring stage. We then analyzed receptor binding site structure and ligands binding poses to describe their interactions. As a result, we devised a simple and straightforward virtual screening Stage II filtering score based on search space extension followed by a geometric estimation of the ligand—binding site fitness. Having this score, we used an ensemble of receptors generated by Hamiltonian Monte Carlo simulation and reported the results. The improvements shown herein prove that our ensemble docking protocol is suited for APJR and can be easily extrapolated to other GPCRs. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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16 pages, 2450 KiB  
Article
Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands
by Boeun Lee, Michelle Taylor, Suzy A. Griffin, Tamara McInnis, Nathalie Sumien, Robert H. Mach and Robert R. Luedtke
Molecules 2021, 26(11), 3182; https://doi.org/10.3390/molecules26113182 - 26 May 2021
Cited by 7 | Viewed by 2594
Abstract
N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was [...] Read more.
N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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23 pages, 6575 KiB  
Article
Ligand-Dependent Conformational Transitions in Molecular Dynamics Trajectories of GPCRs Revealed by a New Machine Learning Rare Event Detection Protocol
by Ambrose Plante and Harel Weinstein
Molecules 2021, 26(10), 3059; https://doi.org/10.3390/molecules26103059 - 20 May 2021
Cited by 12 | Viewed by 3481
Abstract
Central among the tools and approaches used for ligand discovery and design are Molecular Dynamics (MD) simulations, which follow the dynamic changes in molecular structure in response to the environmental condition, interactions with other proteins, and the effects of ligand binding. The need [...] Read more.
Central among the tools and approaches used for ligand discovery and design are Molecular Dynamics (MD) simulations, which follow the dynamic changes in molecular structure in response to the environmental condition, interactions with other proteins, and the effects of ligand binding. The need for, and successes of, MD simulations in providing this type of essential information are well documented, but so are the challenges presented by the size of the resulting datasets encoding the desired information. The difficulty of extracting information on mechanistically important state-to-state transitions in response to ligand binding and other interactions is compounded by these being rare events in the MD trajectories of complex molecular machines, such as G-protein-coupled receptors (GPCRs). To address this problem, we have developed a protocol for the efficient detection of such events. We show that the novel Rare Event Detection (RED) protocol reveals functionally relevant and pharmacologically discriminating responses to the binding of different ligands to the 5-HT2AR orthosteric site in terms of clearly defined, structurally coherent, and temporally ordered conformational transitions. This information from the RED protocol offers new insights into specific ligand-determined functional mechanisms encoded in the MD trajectories, which opens a new and rigorously reproducible path to understanding drug activity with application in drug discovery. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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21 pages, 2899 KiB  
Article
An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement
by Michael P. Killoran, Sergiy Levin, Michelle E. Boursier, Kristopher Zimmerman, Robin Hurst, Mary P. Hall, Thomas Machleidt, Thomas A. Kirkland and Rachel Friedman Ohana
Molecules 2021, 26(10), 2857; https://doi.org/10.3390/molecules26102857 - 12 May 2021
Cited by 4 | Viewed by 5051
Abstract
Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has [...] Read more.
Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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Review

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20 pages, 1074 KiB  
Review
Novel Molecular Targets of Antidepressants
by Małgorzata Jarończyk and Jarosław Walory
Molecules 2022, 27(2), 533; https://doi.org/10.3390/molecules27020533 - 14 Jan 2022
Cited by 16 | Viewed by 5398
Abstract
Antidepressants target a variety of proteins in the central nervous system (CNS), the most important belonging to the family of G-protein coupled receptors and the family of neurotransmitter transporters. The increasing number of crystallographic structures of these proteins have significantly contributed to the [...] Read more.
Antidepressants target a variety of proteins in the central nervous system (CNS), the most important belonging to the family of G-protein coupled receptors and the family of neurotransmitter transporters. The increasing number of crystallographic structures of these proteins have significantly contributed to the knowledge of their mechanism of action, as well as to the design of new drugs. Several computational approaches such as molecular docking, molecular dynamics, and virtual screening are useful for elucidating the mechanism of drug action and are important for drug design. This review is a survey of molecular targets for antidepressants in the CNS and computer based strategies to discover novel compounds with antidepressant activity. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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19 pages, 2523 KiB  
Review
G-Protein Coupled Receptors (GPCRs) in Insects—A Potential Target for New Insecticide Development
by Nannan Liu, Ting Li, Yifan Wang and Shikai Liu
Molecules 2021, 26(10), 2993; https://doi.org/10.3390/molecules26102993 - 18 May 2021
Cited by 25 | Viewed by 5515
Abstract
G-protein coupled receptors (GPCRs) play important roles in cell biology and insects’ physiological processes, toxicological response and the development of insecticide resistance. New information on genome sequences, proteomic and transcriptome analysis and expression patterns of GPCRs in organs such as the central nervous [...] Read more.
G-protein coupled receptors (GPCRs) play important roles in cell biology and insects’ physiological processes, toxicological response and the development of insecticide resistance. New information on genome sequences, proteomic and transcriptome analysis and expression patterns of GPCRs in organs such as the central nervous system in different organisms has shown the importance of these signaling regulatory GPCRs and their impact on vital cell functions. Our growing understanding of the role played by GPCRs at the cellular, genome, transcriptome and tissue levels is now being utilized to develop new targets that will sidestep many of the problems currently hindering human disease control and insect pest management. This article reviews recent work on the expression and function of GPCRs in insects, focusing on the molecular complexes governing the insect physiology and development of insecticide resistance and examining the genome information for GPCRs in two medically important insects, mosquitoes and house flies, and their orthologs in the model insect species Drosophila melanogaster. The tissue specific distribution and expression of the insect GPCRs is discussed, along with fresh insights into practical aspects of insect physiology and toxicology that could be fundamental for efforts to develop new, more effective, strategies for pest control and resistance management. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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19 pages, 2378 KiB  
Review
The GABAB Receptor—Structure, Ligand Binding and Drug Development
by Linn Samira Mari Evenseth, Mari Gabrielsen and Ingebrigt Sylte
Molecules 2020, 25(13), 3093; https://doi.org/10.3390/molecules25133093 - 7 Jul 2020
Cited by 75 | Viewed by 10054
Abstract
The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). [...] Read more.
The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors and Transporters in the CNS as Drug Targets)
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