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Allosteric Modulator
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Allosteric Modulator

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

Deadline for manuscript submissions: closed (15 January 2020) | Viewed by 12328

Special Issue Editor

Dr. Robert J. Doerksen

E-Mail Website
Guest Editor
Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
Interests: computational medicinal chemistry; cannabinoid receptors; drug discovery; quantum chemistry; allosteric modulators; protein modeling; quantitative structure–activity relationships
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although the effects of allosteric modulators are, by definition, indirect, nevertheless they can be fundamentally, pharmacologically, and clinically-significant to the functioning of the proteins and of the agonists or inverse agonists that they modulate. Positive modulation can enhance the binding affinity and/or efficacy of agonists, whether endogenous or exogenous, and negative allosteric modulation can have the opposite effect. There can also be silent allosteric modulators. An important early example is benzodiazepine drugs, which act as positive allosteric modulators to enhance ion flow through GABA-activated GABAA receptors. A recent hot area of study is of negative allosteric modulators of the cannabinoid receptor 1 to enable enhanced control of downstream signalling. Allosteric binding pockets can be adjacent to or more distant from the orthosteric pockets. The effects of allosteric modulators are often thought to be mediated by induced conformational changes in the protein, which can cause enhanced or constricted access and binding of the agonist to the orthosteric binding pocket. However, it also can be helpful to think of the protein as existing in an ensemble of states which can be selectively stabilized by small molecules or proteins of various modulating natures.

This Special Issue will present new research and reviews on allosteric modulators, with a focus on design of such modulators, modelling and experimental study of their structures and interactions with proteins and agonists, and the pharmacological effects that result, such as biased signalling.

Dr. Robert J. Doerksen
Guest Editor

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Keywords

  • allosteric modulators
  • protein-ligand interactions
  • allosteric regulation
  • protein modeling
  • drug discovery

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Published Papers (3 papers)

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Research

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15 pages, 3181 KiB  
Article
Revisiting the Allosteric Regulation of Sodium Cation on the Binding of Adenosine at the Human A2A Adenosine Receptor: Insights from Supervised Molecular Dynamics (SuMD) Simulations
by Maicol Bissaro, Giovanni Bolcato, Giuseppe Deganutti, Mattia Sturlese and Stefano Moro
Molecules 2019, 24(15), 2752; https://doi.org/10.3390/molecules24152752 - 29 Jul 2019
Cited by 7 | Viewed by 4302
Abstract
One of the most intriguing findings highlighted from G protein-coupled receptor (GPCR) crystallography is the presence, in many members of class A, of a partially hydrated sodium ion in the middle of the seven transmembrane helices (7TM) bundle. In particular, the human adenosine [...] Read more.
One of the most intriguing findings highlighted from G protein-coupled receptor (GPCR) crystallography is the presence, in many members of class A, of a partially hydrated sodium ion in the middle of the seven transmembrane helices (7TM) bundle. In particular, the human adenosine A2A receptor (A2A AR) is the first GPCR in which a monovalent sodium ion was crystallized in a distal site from the canonical orthosteric one, corroborating, from a structural point of view, its role as a negative allosteric modulator. However, the molecular mechanism by which the sodium ion influences the recognition of the A2A AR agonists is not yet fully understood. In this study, the supervised molecular dynamics (SuMD) technique was exploited to analyse the sodium ion recognition mechanism and how its presence influences the binding of the endogenous agonist adenosine. Due to a higher degree of flexibility of the receptor extracellular (EC) vestibule, we propose the sodium-bound A2A AR as less efficient in stabilizing the adenosine during the different steps of binding. Full article
(This article belongs to the Special Issue Allosteric Modulator)
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10 pages, 944 KiB  
Article
Acute Administration of Desformylflustrabromine Relieves Chemically Induced Pain in CD-1 Mice
by Loni A. Weggel and Anshul A. Pandya
Molecules 2019, 24(5), 944; https://doi.org/10.3390/molecules24050944 - 7 Mar 2019
Cited by 5 | Viewed by 2732
Abstract
Neuronal nicotinic acetylcholine receptors are cell membrane-bound ion channels that are widely distributed in the central nervous system. The α4β2 subtype of neuronal nicotinic acetylcholine receptor plays an important role in modulating the signaling pathways for pain. Previous studies have shown that agonists, [...] Read more.
Neuronal nicotinic acetylcholine receptors are cell membrane-bound ion channels that are widely distributed in the central nervous system. The α4β2 subtype of neuronal nicotinic acetylcholine receptor plays an important role in modulating the signaling pathways for pain. Previous studies have shown that agonists, partial agonists, and positive allosteric modulators for the α4β2 receptors are effective in relieving pain. Desformylflustrabromine is a compound that acts as an allosteric modulator of α4β2 receptors. The aim of this study was to assess the effects of desformylflustrabromine on chemically induced pain. For this purpose, the formalin-induced pain test and the acetic acid-induced writhing response test were carried out in CD-1 mice. Both tests represent chemical assays for nociception. The results show that desformylflustrabromine is effective in producing an analgesic effect in both tests used for assessing nociception. These results suggest that desformylflustrabromine has the potential to become a clinically used drug for pain relief. Full article
(This article belongs to the Special Issue Allosteric Modulator)
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Review

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22 pages, 4742 KiB  
Review
Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors
by Claudia Llinas del Torrent, Laura Pérez-Benito and Gary Tresadern
Molecules 2019, 24(6), 1098; https://doi.org/10.3390/molecules24061098 - 20 Mar 2019
Cited by 11 | Viewed by 4450
Abstract
Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular [...] Read more.
Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work. Full article
(This article belongs to the Special Issue Allosteric Modulator)
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