Computational Methods in Drug Design: Modeling G Protein-Coupled Receptor Monomers, Dimers, and Oligomers

Reggio, PH

doi:10.1208/aapsj080237

Cited by 8 publications

(9 citation statements)

References 120 publications

(129 reference statements)

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“…59 Characterization of the CXCR4 crystal structure in the presence of small antagonists also supports the hypothesis of receptor dimerization, and suggests that additional interactions between CXCR4 dimers generate higher order complexes. 60 According to structural data, dimer association is driven mostly by hydrophobic interactions between residues included in transmembrane (TM)-V and -VI, 60 in contrast to previous models of GPCR, which suggest contacts through TM-I, TM-IV, and TM-V. [61][62][63] In silico analysis on CCR5 identified Val64 in TM-I and I164 in TM-IV as key residues for dimerization and function. Mutation of these residues in CCR5 blocks dimerization and the response to CCL5 stimulus.…”

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 97%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention.

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Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 97%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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“…58 Complete details on the generation of the activated state models were published and properly described by them in the literature. 43,46,59,60 Docking Studies. Minimum energy conformers of each ligand were selected for the initial docking.…”

Section: ■ Associated Contentmentioning

confidence: 99%

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

et al. 2016

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A combination of molecular modeling and structure–activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

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“…However, cannabinoid receptors share only 20-21% sequence identity with bovine rhodopsin. Despite this, modelling has contributed a great deal to current understanding of cannabinoid ligand-receptor interactions [159][160][161][162][163][164][165], including CBII [166][167][168], and have helped explain why some ligands are selective for one receptor over another [160,166,167,169].…”

Section: The Development Of Cbii-selective Ago-nistsmentioning

confidence: 99%

The Development of Cannabinoid CBII Receptor Agonists for the Treatment of Central Neuropathies

Rivers¹,

Ashton

2010

CNSAMC

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Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer's disease and Parkinson's disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR).

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Computational Methods in Drug Design: Modeling G Protein-Coupled Receptor Monomers, Dimers, and Oligomers

Cited by 8 publications

References 120 publications

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

The Development of Cannabinoid CBII Receptor Agonists for the Treatment of Central Neuropathies

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