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GPCRs: Ligands and beyond 2022

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 46750

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Dr. Erika Cione

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Interests: vitamin A and its provitamin; microRNAs; gene expression; ketogenic diet; lipedema; cognitive and neurodegeneration
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Dr. Maria Cristina Caroleo

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Department of Health Sciences, University of Magna Graecia Catanzaro, 88100 Catanzaro, Italy
Interests: immune system; pharmacology; cell signaling; COVID 19
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Special Issue Information

Dear Colleagues,

Tremendous progress has seen in the recent years in the elucidation of experimental structural information for G-protein coupled receptors (GPCRs). The main stream of pharmaceutically relevant GPCRs structural information is accessible by homology models that progressively increase the structural information. This fostered the application of structure-based drug design tools for this emerging class of drug targets. Likewise, is still going the discovery of natural compounds and/or endogenous ligands molecules on GPCRs. Of interest GPCR: i) expression; ii) signaling; iii) molecule interaction; iv) molecular dynamics; v) docking; in physiological and pathophysiological models.

Dr. Erika Cione
Dr. Maria Cristina Caroleo
Guest Editors

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Related Special Issue

GPCR Based Drug Discovery in Pharmaceuticals (16 articles)

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 189 KiB

Open AccessEditorial

Special Issue “GPCRs: Ligands and beyond 2022”

by Erika Cione and Maria Cristina Caroleo

Pharmaceuticals 2022, 15(6), 647; https://doi.org/10.3390/ph15060647 - 24 May 2022

Viewed by 1453

Abstract

The human genome encodes more than 800 different G protein-coupled receptors (GPCRs), uncovering their importance in human physiology [...] Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

Research

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11 pages, 4542 KiB

Open AccessArticle

Sodium or Not Sodium: Should Its Presence Affect the Accuracy of Pose Prediction in Docking GPCR Antagonists?

by Davide Bassani, Matteo Pavan, Mattia Sturlese and Stefano Moro

Pharmaceuticals 2022, 15(3), 346; https://doi.org/10.3390/ph15030346 - 11 Mar 2022

Cited by 7 | Viewed by 2737

Abstract

The function of the allosteric sodium ion in stabilizing the inactive form of GPCRs has been extensively described in the past decades. Its presence has been reported to be essential for the binding of antagonist molecules in the orthosteric site of these very important therapeutical targets. Among the GPCR–antagonist crystal structures available, in most cases, the sodium ion could not be experimentally resolved, obliging computational scientists using GPCRs as targets for virtual screening to ask: “Should the sodium ion affect the accuracy of pose prediction in docking GPCR antagonists?” In the present study, we examined the performance of three orthogonal docking programs in the self-docking of GPCR antagonists to try to answer this question. The results of the present work highlight that if the sodium ion is resolved in the crystal structure used as the target, it should also be taken into account during the docking calculations. If the crystallographic studies were not able to resolve the sodium ion then no advantage would be obtained if this is manually inserted in the virtual target. The outcomes of the present analysis are useful for researchers exploiting molecular docking-based virtual screening to efficiently identify novel GPCR antagonists. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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30 pages, 13413 KiB

Open AccessArticle

The Novel Application of Geometric Morphometrics with Principal Component Analysis to Existing G Protein-Coupled Receptor (GPCR) Structures

by Daniel N. Wiseman, Nikita Samra, María Monserrat Román Lara, Samantha C. Penrice and Alan D. Goddard

Pharmaceuticals 2021, 14(10), 953; https://doi.org/10.3390/ph14100953 - 23 Sep 2021

Cited by 6 | Viewed by 4072

Abstract

The G protein-coupled receptor (GPCR) superfamily is a large group of membrane proteins which, because of their vast involvement in cell signalling pathways, are implicated in a plethora of disease states and are therefore considered to be key drug targets. Despite advances in techniques to study these receptors, current prophylaxis is often limited due to the challenging nature of their dynamic, complex structures. Greater knowledge and understanding of their intricate structural rearrangements will therefore undoubtedly aid structure-based drug design against GPCRs. Disciplines such as anthropology and palaeontology often use geometric morphometrics to measure variation between shapes and we have therefore applied this technique to analyse GPCR structures in a three-dimensional manner, using principal component analysis. Our aim was to create a novel system able to discriminate between GPCR structures and discover variation between them, correlated with a variety of receptor characteristics. This was conducted by assessing shape changes at the extra- and intracellular faces of the transmembrane helix bundle, analysing the XYZ coordinates of the amino acids at those positions. We have demonstrated that GPCR structures can be classified based on characteristics such as activation state, bound ligands and fusion proteins, with the most significant results focussed at the intracellular face. Conversely, our analyses provide evidence that thermostabilising mutations do not cause significant differences when compared to non-mutated GPCRs. We believe that this is the first time geometric morphometrics has been applied to membrane proteins on this scale, and believe it can be used as a future tool in sense-checking newly resolved structures and planning experimental design. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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19 pages, 3108 KiB

Open AccessArticle

Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

by David Méndez-Luna, Loreley Araceli Morelos-Garnica, Juan Benjamín García-Vázquez, Martiniano Bello, Itzia Irene Padilla-Martínez, Manuel Jonathan Fragoso-Vázquez, Alfonso Dueñas González, Nuria De Pedro, José Antonio Gómez-Vidal, Humberto Lubriel Mendoza-Figueroa and José Correa-Basurto

Pharmaceuticals 2021, 14(1), 49; https://doi.org/10.3390/ph14010049 - 10 Jan 2021

Cited by 11 | Viewed by 3430

Abstract

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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12 pages, 1757 KiB

Open AccessArticle

Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1

by Marius Ozenil, Jonas Aronow, Daniela Piljak, Chrysoula Vraka, Wolfgang Holzer, Helmut Spreitzer, Wolfgang Wadsak, Marcus Hacker and Verena Pichler

Pharmaceuticals 2020, 13(12), 437; https://doi.org/10.3390/ph13120437 - 30 Nov 2020

Cited by 6 | Viewed by 3454

Abstract

Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco’s phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. K_i values toward M1 were determined as 99 ± 19 nM, 800 ± 200 nM, and 380 ± 90 nM for the (R,R)-, (S,S)-, and racemic (R,S)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (R,R)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest K_i value. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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16 pages, 6291 KiB

Open AccessArticle

New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding

by Bahareh Rasaeifar, Patricia Gomez-Gutierrez and Juan J. Perez

Pharmaceuticals 2020, 13(8), 197; https://doi.org/10.3390/ph13080197 - 17 Aug 2020

Cited by 4 | Viewed by 3224

Abstract

Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, only a few small molecule binders have been disclosed so far, hampering a deeper understanding of their pharmacology. In order to have a deeper understanding of the stereochemical features characterizing binding to the BB1 receptor, we performed the molecular modeling study consisting of the construction of a 3D model of the receptor by homology modeling followed by a docking study of the peptoids PD168368 and PD176252 onto it. Analysis of the complexes permitted us to propose prospective bound conformations of the compounds, consistent with the experimental information available. Subsequently, we defined a pharmacophore describing minimal stereochemical requirements for binding to the BB1 receptor that was used in silico screening. This exercise yielded a set of small molecules that were purchased and tested, showing affinity to the BB1 but not to the BB2 receptor. These molecules exhibit scaffolds of diverse chemical families that can be used as a starting point for the development of novel BB1 antagonists. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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Review

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18 pages, 1267 KiB

Open AccessReview

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

by Hsi-Hsien Lin, Kwai-Fong Ng, Tse-Ching Chen and Wen-Yi Tseng

Pharmaceuticals 2022, 15(2), 219; https://doi.org/10.3390/ph15020219 - 11 Feb 2022

Cited by 25 | Viewed by 4824

Abstract

Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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27 pages, 6871 KiB

Open AccessReview

Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery

by R. N. V. Krishna Deepak, Ravi Kumar Verma, Yossa Dwi Hartono, Wen Shan Yew and Hao Fan

Pharmaceuticals 2022, 15(1), 12; https://doi.org/10.3390/ph15010012 - 22 Dec 2021

Cited by 13 | Viewed by 7484

Abstract

Great progress has been made over the past decade in understanding the structural, functional, and pharmacological diversity of lipid GPCRs. From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology. The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened our comprehension of the structural and functional facets of the receptor family members and has helped usher in a modern age of structure-based drug design and development. First, we provide a primer on lipid mediators and lipid GPCRs and their role in physiology and diseases as well as their value as drug targets. Second, we summarize the current advancements in the understanding of structural features of lipid GPCRs, such as the structural variation of their extracellular domains, diversity of their orthosteric and allosteric ligand binding sites, and molecular mechanisms of ligand binding. Third, we close by collating the emerging paradigms and opportunities in targeting lipid GPCRs, including a brief discussion on current strategies, challenges, and the future outlook. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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20 pages, 1771 KiB

Open AccessReview

Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases

by Salomé Gonçalves-Monteiro, Rita Ribeiro-Oliveira, Maria Sofia Vieira-Rocha, Martin Vojtek, Joana B. Sousa and Carmen Diniz

Pharmaceuticals 2021, 14(5), 439; https://doi.org/10.3390/ph14050439 - 7 May 2021

Cited by 10 | Viewed by 4830

Abstract

G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the nucleus as an autonomous signaling organelle (triggered by GPCRs). Nuclear GPCRs are involved in physiological (namely cell proliferation, transcription, angiogenesis and survival) and disease processes (cancer, cardiovascular diseases, etc.). In this review we summarize emerging evidence on nuclear GPCRs expression/function (with some nuclear GPCRs evidencing atypical/disruptive signaling pathways) in non-communicable disease, thus, bringing nuclear GPCRs as targets to the forefront of debate. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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11 pages, 833 KiB

Open AccessReview

Hemorphins Targeting G Protein-Coupled Receptors

by Mohammed Akli Ayoub and Ranjit Vijayan

Pharmaceuticals 2021, 14(3), 225; https://doi.org/10.3390/ph14030225 - 7 Mar 2021

Cited by 12 | Viewed by 2695

Abstract

Hemorphins are short peptides produced by the proteolysis of the beta subunit of hemoglobin. These peptides have diverse physiological effects especially in the nervous and the renin-angiotensin systems. Such effects occur through the modulation of a diverse range of proteins including enzymes and receptors. In this review, we focus on pharmacological and functional targeting of G protein-coupled receptors (GPCRs) by hemorphins and their implication in physiology and pathophysiology. Among GPCRs, the opioid receptors constitute the first set of targets of hemorphins with implication in analgesia. Subsequently, several other GPCRs have been reported to be directly or indirectly involved in hemorphins’ action. This includes the receptors for angiotensin II, oxytocin, bombesin, and bradykinin, as well as the human MAS-related G protein-coupled receptor X1. Interestingly, both orthosteric activation and allosteric modulation of GPCRs by hemorphins have been reported. This review links hemorphins with GPCR pharmacology and signaling, supporting the implication of GPCRs in hemorphins’ effects. Thus, this aids a better understanding of the molecular basis of the action of hemorphins and further demonstrates that hemorphin-GPCR axis constitutes a valid target for therapeutic intervention in different systems. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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14 pages, 2337 KiB

Open AccessReview

Tumor Immunotherapy Using A_2A Adenosine Receptor Antagonists

by Jinfeng Zhang, Wenzhong Yan, Wenwen Duan, Kurt Wüthrich and Jianjun Cheng

Pharmaceuticals 2020, 13(9), 237; https://doi.org/10.3390/ph13090237 - 8 Sep 2020

Cited by 24 | Viewed by 6239

Abstract

The A_2A adenosine receptor (A_2AAR) plays critical roles in human physiology and pathophysiology, which makes it an important drug target. Previous drug-discovery efforts targeting the A_2AAR have been focused on the use of A_2AAR antagonists for the treatment of Parkinson’s disease. More recently, the A_2AAR has attracted additional attention for its roles in immuno-oncology, and a number of A_2AAR antagonists are currently used as lead compounds for antitumor drugs in both preclinical models and clinical trials. This review surveys recent advances in the development of A_2AAR antagonists for cancer immunotherapy. The therapeutic potential of representative A_2AAR antagonists is discussed based on both animal efficacy studies and clinical data. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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