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Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled...
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Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 16095

Special Issue Editors

Dr. Livia Basile

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Guest Editor
Department of Health and Drug Sciences, University of Catania, Viale A. Doria 6 ed. 2, I-95125 Catania, Italy
Interests: rational drug design; virtual screening and drug repositioning; computational chemistry and biochemistry; in silico and in vitro blood–brain barrier (BBB) permeation
Prof. Dr. Salvatore Guccione

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Guest Editor
Department of Health and Drug Sciences, University of Catania, Viale A. Doria 6 ed. 2, I-95125 Catania, Italy
Interests: rational drug design; synthetic medicinal chemistry; virtual screening and drug repositioning; computational chemistry and biochemistry

Special Issue Information

Dear Colleagues,

G-protein-coupled receptors (GPCRs) are involved in many physiological functions via signal transduction and direct or indirect control of cellular interplay. GPCRs are the targets of many clinically important drugs (>60%). The GPCR field has tremendous potential for drug discovery. Probing the determinants of the interactions between GPCRs and ligands, which take advantage of ortho- or allosteric interactions and can switch on bias (via functional selectivity), is central to drug discovery.

Mutations or alterations in GPCRs can cause different diseases. Understanding the molecular basis of GPCR dynamics and their alternate functioning may help us better understand different human diseases and so improve the likelihood of finding compounds with which health can be recovered.

All of the above considerations will lead to further development in this field, which mixes knowledge that comes from experimental and in-silico methodologies.

Dr. Livia Basile
Prof. Dr. Salvatore Guccione
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • physiological and pathological role
  • GPCR mutation and diseases
  • understanding the molecular basis of GPCRs’ mechanism of action and ligand binding
  • in silico and experimental approaches
  • perspectives on social impact and rare diseases

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Published Papers (6 papers)

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Research

20 pages, 4152 KiB  
Article
Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized 129Xe NMR
by Peter Schmidt, Alexander Vogel, Benedikt Schwarze, Florian Seufert, Kai Licha, Virginia Wycisk, Wolfgang Kilian, Peter W. Hildebrand and Lorenz Mitschang
Molecules 2023, 28(3), 1424; https://doi.org/10.3390/molecules28031424 - 2 Feb 2023
Cited by 2 | Viewed by 1794
Abstract
G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and [...] Read more.
G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized 129Xe for the detection of the conformational states of human neuropeptide Y2 receptor is introduced. The xenon trapping cage molecule cryptophane-A attached to a cysteine in extracellular loop 2 of the receptor facilitates chemical exchange saturation transfer experiments without and in the presence of native ligand neuropeptide Y. High-quality spectra indicative of structural states of the receptor–cage conjugate were obtained. Specifically, five signals could be assigned to the conjugate in the apo form. After the addition of NPY, one additional signal and subtle modifications in the persisting signals could be detected. The correlation of the spectroscopic signals and structural states was achieved with molecular dynamics simulations, suggesting frequent contact between the xenon trapping cage and the receptor surface but a preferred interaction with the bound ligand. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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16 pages, 153065 KiB  
Article
Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands
by Wojciech Pietruś, Rafał Kurczab, Dawid Warszycki, Andrzej J. Bojarski and Jürgen Bajorath
Molecules 2023, 28(2), 490; https://doi.org/10.3390/molecules28020490 - 4 Jan 2023
Cited by 4 | Viewed by 1715
Abstract
Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug [...] Read more.
Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database—FiSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 FiSAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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13 pages, 1807 KiB  
Communication
G-Protein Coupled Receptors in Human Sperm: An In Silico Approach to Identify Potential Modulatory Targets
by Pedro O. Corda, Joana Santiago and Margarida Fardilha
Molecules 2022, 27(19), 6503; https://doi.org/10.3390/molecules27196503 - 1 Oct 2022
Cited by 5 | Viewed by 2772
Abstract
G protein-coupled receptors (GPCRs) are involved in several physiological processes, and they represent the largest family of drug targets to date. However, the presence and function of these receptors are poorly described in human spermatozoa. Here, we aimed to identify and characterize the [...] Read more.
G protein-coupled receptors (GPCRs) are involved in several physiological processes, and they represent the largest family of drug targets to date. However, the presence and function of these receptors are poorly described in human spermatozoa. Here, we aimed to identify and characterize the GPCRs present in human spermatozoa and perform an in silico analysis to understand their potential role in sperm functions. The human sperm proteome, including proteomic studies in which the criteria used for protein identification was set as <5% FDR and a minimum of 2 peptides match per protein, was crossed with the list of GPCRs retrieved from GLASS and GPCRdb databases. A total of 71 GPCRs were identified in human spermatozoa, of which 7 had selective expression in male tissues (epididymis, seminal vesicles, and testis), and 9 were associated with male infertility defects in mice. Additionally, ADRA2A, AGTR1, AGTR2, FZD3, and GLP1R were already associated with sperm-specific functions such as sperm capacitation, acrosome reaction, and motility, representing potential targets to modulate and improve sperm function. Finally, the protein-protein interaction network for the human sperm GPCRs revealed that 24 GPCRs interact with 49 proteins involved in crucial processes for sperm formation, maturation, and fertilization. This approach allowed the identification of 8 relevant GPCRs (ADGRE5, ADGRL2, GLP1R, AGTR2, CELSR2, FZD3, CELSR3, and GABBR1) present in human spermatozoa that can be the subject of further investigation to be used even as potential modulatory targets to treat male infertility or to develop new non-hormonal male contraceptives. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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23 pages, 7283 KiB  
Article
In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic Photoactive Ligands
by Beata Niklas, Bruno Lapied and Wieslaw Nowak
Molecules 2022, 27(10), 3280; https://doi.org/10.3390/molecules27103280 - 20 May 2022
Cited by 3 | Viewed by 2214
Abstract
Insect vector-borne diseases pose serious health problems, so there is a high demand for efficient molecules that could reduce transmission. Using molecular docking and molecular dynamics (MD) simulation, we studied a series of compounds acting on human and insect muscarinic acetylcholine receptors (mAChRs), [...] Read more.
Insect vector-borne diseases pose serious health problems, so there is a high demand for efficient molecules that could reduce transmission. Using molecular docking and molecular dynamics (MD) simulation, we studied a series of compounds acting on human and insect muscarinic acetylcholine receptors (mAChRs), a novel target of synergistic agents in pest control. We characterized early conformational changes of human M1 and fruit fly type-A mAChR G protein-coupled receptors (GPCRs) in response to DEET, IR3535, and muscarine binding based on the MD analysis of the activation microswitches known to form the signal transduction pathway in class A GPCRs. We indicated groups of microswitches that are the most affected by the presence of a ligand. Moreover, to increase selectivity towards insects, we proposed a new, bitopic, photoswitchable mAChR ligand—BQCA-azo-IR353 and studied its interactions with both receptors. Modeling data showed that using a bitopic ligand may be a promising strategy in the search for better insect control. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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26 pages, 6258 KiB  
Article
Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1
by Barbara Knapp, Jens Roedig, Heiko Roedig, Jacek Krzysko, Nicola Horn, Baran E. Güler, Deva Krupakar Kusuluri, Adem Yildirim, Karsten Boldt, Marius Ueffing, Ines Liebscher and Uwe Wolfrum
Molecules 2022, 27(10), 3108; https://doi.org/10.3390/molecules27103108 - 12 May 2022
Cited by 10 | Viewed by 4184
Abstract
The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible [...] Read more.
The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible knowledge of the molecular function and signaling of VLGR1, the pathomechanisms underlying the development of these diseases are still unknown. Our study aimed to identify novel, previously unknown protein networks associated with VLGR1 in order to describe new functional cellular modules of this receptor. Using affinity proteomics, we have identified numerous new potential binding partners and ligands of VLGR1. Tandem affinity purification hits were functionally grouped based on their Gene Ontology terms and associated with functional cellular modules indicative of functions of VLGR1 in transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance. In addition, we validated the identified protein interactions and pathways in vitro and in situ. Our data provided new insights into possible functions of VLGR1, related to the development of USH and epilepsy, and also suggest a possible role in the development of other neuronal diseases such as Alzheimer’s disease. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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22 pages, 4002 KiB  
Article
Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treatment of Rheumatoid Arthritis
by Letizia Crocetti, Claudia Vergelli, Gabriella Guerrini, Maria Paola Giovannoni, Liliya N. Kirpotina, Andrei I. Khlebnikov, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Elena Lucarini, Igor A. Schepetkin and Mark T. Quinn
Molecules 2021, 26(21), 6583; https://doi.org/10.3390/molecules26216583 - 30 Oct 2021
Cited by 7 | Viewed by 2196
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the [...] Read more.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week. Full article
(This article belongs to the Special Issue Molecular Modeling, Synthesis, and Functional Characterization of GPCR (G-Protein Coupled Receptor) Ligands)
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