Advances in G Protein-Coupled Receptors Biophysical and Medicinal Chemistry

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Pharmaceutical Science".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 10621

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SMART Lab - Scuola Normale Superiore di Pisa, Palazzo D'Ancona, Via Consoli del Mare 1, 56126 Pisa, Italy
Interests: physical chemistry; biophysics; chemical biology; medicinal chemistry; biochemistry

Special Issue Information

Dear Colleagues,

The largest family of human cell surface proteins, which is known as guanine nucleotide-binding protein coupled receptors (GPCRs), play important roles in biological processes such as vision, sensing and neurotransmission. In adrenergic receptors, a subfamily of GPCRs that can be found in many cells, the binding of a catecholamine, especially norepinephrine (noradrenaline) and epinephrine (adrenaline), can stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity and a variety of metabolic and central nervous system functions. Moreover, GPCRs have also been found to be actively involved in cancer growth and development. Numerous extracellular molecules, including hormones and drugs, can activate and inactivate GPCRs acting as agonists and antagonists, respectively, the former usually leading to conformational changes associated with specific protein functions. Agonists and antagonists interacting with adrenergic receptors have been successfully employed in the treatment of various diseases, such as hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy and glaucoma. Given their implication in different human diseases, GPCRs have become the target of about 35% of all marketed pharmaceutical drugs in the US and worldwide.

During the last two decades, thanks to technological advances in crystallization methods, the X-ray crystal structures of GPCRs have been released in an exponential manner. In 2012, Robert Lefkowitz and Brian Kobilka were awarded the Nobel Prize in Chemistry for their groundbreaking discoveries revealing the structure and function of GPCRs at a molecular level. More than 150 GPCR structures published in the Protein Data Bank are co-crystallized with ligands. Contemporaneously, an increasing number of homology models has also contributed to covering more than 10% of the GPCR superfamily. Over the last ten years, experimental and computational studies have proven that adrenergic receptors act as amplifiers of signals from the extracellular environment to intracellular proteins, even when activated by agonists, with a conformational heterogeneity in which inactive, intermediate and active states coexist. Furthermore, GPCRs have also started to be seen as allosteric machines, which can be activated not only by agonists but also by ions, lipids, cholesterol and water.

Since understanding receptor–drug interactions at an atomic level is essential in structure-based drug discovery (SBDD), molecular docking and molecular dynamics (MD) simulations have become widely employed tools to aid drug design by revealing binding affinity, reaction mechanism and protein–ligand interactions. This Special Issue aims at gathering original contributions describing the biophysical properties and the interaction of GPCRs with biologically relevant molecules and drugs. Research articles using both computational and experimental approaches are particularly welcome.

Dr. Andrea Catte
Guest Editor

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Keywords

  • GPCRs
  • ligand-receptor interactions
  • allosteric modulation
  • structure-based drug design
  • computer-aided drug design
  • molecular docking
  • molecular dynamics simulations

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Published Papers (3 papers)

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30 pages, 44638 KiB  
Article
L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β2-Adrenergic Receptor
by Andrea Catte, Akash Deep Biswas, Giordano Mancini and Vincenzo Barone
Life 2022, 12(9), 1393; https://doi.org/10.3390/life12091393 - 6 Sep 2022
Cited by 1 | Viewed by 2722
Abstract
The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to β2-adrenergic receptor (β2AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, [...] Read more.
The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to β2-adrenergic receptor (β2AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human β2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible β2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into β2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 μs MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF. Full article
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19 pages, 5679 KiB  
Article
Behavior of Chemokine Receptor 6 (CXCR6) in Complex with CXCL16 Soluble form Chemokine by Molecular Dynamic Simulations: General Protein‒Ligand Interaction Model and 3D-QSAR Studies of Synthetic Antagonists
by Giovanny Aguilera-Durán and Antonio Romo-Mancillas
Life 2021, 11(4), 346; https://doi.org/10.3390/life11040346 - 15 Apr 2021
Cited by 7 | Viewed by 4707
Abstract
The CXCR6‒CXCL16 axis is involved in several pathological processes, and its overexpression has been detected in different types of cancer, such as prostate, breast, ovary, and lung cancer, along with schwannomas, in which it promotes invasion and metastasis. Moreover, this axis is involved [...] Read more.
The CXCR6‒CXCL16 axis is involved in several pathological processes, and its overexpression has been detected in different types of cancer, such as prostate, breast, ovary, and lung cancer, along with schwannomas, in which it promotes invasion and metastasis. Moreover, this axis is involved in atherosclerosis, type 1 diabetes, primary immune thrombocytopenia, vitiligo, and other autoimmune diseases, in which it is responsible for the infiltration of different immune system cells. The 3D structure of CXCR6 and CXCL16 has not been experimentally resolved; therefore, homology modeling and molecular dynamics simulations could be useful for the study of this signaling axis. In this work, a homology model of CXCR6 and a soluble form of CXCL16 (CXCR6‒CXCL16s) are reported to study the interactions between CXCR6 and CXCL16s through coarse-grained molecular dynamics (CG-MD) simulations. CG-MD simulations showed the two activation steps of CXCR6 through a decrease in the distance between the chemokine and the transmembrane region (TM) of CXCR6 and transmembrane rotational changes and polar interactions between transmembrane segments. The polar interactions between TM3, TM5, and TM6 are fundamental to functional conformation and the meta-active state of CXCR6. The interactions between D77-R280 and T243-TM7 could be related to the functional conformation of CXCR6; alternatively, the interaction between Q195-Q244 and N248 could be related to an inactive state due to the loss of this interaction, and an arginine cage broken in the presence of CXCL16s allows the meta-active state of CXCR6. A general protein‒ligand interaction supports the relevance of TM3‒TM5‒TM6 interactions, presenting three relevant pharmacophoric features: HAc (H-bond acceptor), HDn (H-bond donator), and Hph (hydrophobic), distributed around the space between extracellular loops (ECLs) and TMs. The HDn feature is close to TM3 and TM6; likewise, the HAc and Hph features are close to ECL1 and ECL2 and could block the rotation and interactions between TM3‒TM6 and the interactions of CXCL16s with the ECLs. Tridimensional quantitative structure-activity relationships (3D-QSAR) models show that the positive steric (VdW) and electrostatic fields coincide with the steric and positive electrostatic region of the exo-azabicyclo[3.3.1]nonane scaffold in the best pIC50 ligands. This substructure is close to the E274 residue and therefore relevant to the activity of CXCR6. These data could help with the design of new molecules that inhibit chemokine binding or antagonize the receptor based on the activation mechanism of CXCR6 and provoke a decrease in chemotaxis caused by the CXCR6‒CXCL16 axis. Full article
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10 pages, 4372 KiB  
Case Report
Extrathyroidal Manifestations of Persistent Sporadic Non-Autoimmune Hyperthyroidism in a 6-Year-Old Boy: A Case Report
by Moon Bae Ahn
Life 2021, 11(7), 713; https://doi.org/10.3390/life11070713 - 19 Jul 2021
Cited by 1 | Viewed by 2236
Abstract
Thyroid-stimulating hormone receptor (TSHR) belongs in a subfamily of the G protein-coupled receptors. Thyroid-stimulating hormone receptor gene (TSHR), a gene encoding TSHR, is a major controller of thyroid cell metabolism, and its gain of function mutation leads to non-autoimmune hyperthyroidism (NAH), [...] Read more.
Thyroid-stimulating hormone receptor (TSHR) belongs in a subfamily of the G protein-coupled receptors. Thyroid-stimulating hormone receptor gene (TSHR), a gene encoding TSHR, is a major controller of thyroid cell metabolism, and its gain of function mutation leads to non-autoimmune hyperthyroidism (NAH), a condition of a prolonged state of hyperthyroidism. Diverse human diseases, and genetic, constitutional, or environmental factors contribute to the phenotypic variations of TSHR mutations; however, the underlying mechanisms leading to various extrathyroidal manifestations across ages are poorly understood. In 2018, the first Korean case of persistent sporadic NAH due to missense mutation of TSHR was reported, and this report highlights the extrathyroidal manifestations of NAH. Further investigation is warranted to clarify the roles of functional mutations of TSHR by investigating the correlation between G protein-dependent signaling properties and clinical phenotypes associated with persistent hyperthyroidism in order to develop novel therapies that could be provided for numerous conditions caused by NAH. Full article
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