Methods for the Development of In Silico GPCR Models

Morales, Paula; Hurst, Dow P.; Reggio, Patricia H.

doi:10.1016/bs.mie.2017.05.005

Cited by 17 publications

(17 citation statements)

References 112 publications

(172 reference statements)

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“…Our collaborators, Morales et al [3] have recently developed an in silico model of GPR3. In developing the model, they hope to gain insight into the structure and function of GPR3 and use the model as a powerful tool for the development of high-affinity/ potency ligands for the receptor.…”

Section: Significance and Implicationsmentioning

confidence: 99%

“…These three receptors share approximately 60% amino acid identity [1]. They are also phylogenetically related to the spingosine-1-phosphate (S1P) receptor, lysophosphatidic acid receptor, melanocortin receptor, and cannabinoid receptors [2,3]. Despite being related, the similarity of GPR3, GPR6, and GPR12 to other receptor groups is not sufficient to suggest a common ligand.…”

Section: Introductionmentioning

confidence: 99%

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GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

et al. 2018

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The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions. Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer's disease, Parkinson's disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.

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Section: Significance and Implicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

et al. 2018

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“…GPR3, GPR6 and GPR12 also contain highly conserved residues in the transmembrane helices such as N1.50, D2.50, R3.50, W4.50, P6.50, and P7.50. In addition, they preserve the specific motifs present in TMH3, TMH6 and TMH7 which are DRY, CWXP, and NPXXY motifs, respectively (Morales et al 2017a). …”

Section: General Features: Structure and Expressionmentioning

confidence: 99%

“…Although no crystal structure has been reported yet for any of these orphan receptors, computational molecular models are being developed based on GPCRs with currently available crystal structures (Morales et al 2017a). These homology models take into consideration structural differences and similarities with other GPCRs while identifying potential binding pocket residues for GPR3, GPR6 and GPR12.…”

Section: General Features: Structure and Expressionmentioning

confidence: 99%

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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GPR3, GPR6 and GPR12 are three orphan receptors that belong to the Class A family of G protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship GPR3, GPR6 and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data is required to confirm this association. GPR3, GPR6 and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6 and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

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“…The IC conformational changes due to the β-arrestin activation mechanism are not fully elucidated and studied as G-protein activation among GPCRs. It has been suggested that conformational changes occur in TMH7-Hx8 domains accompanying β-arrestin signaling [49,50], with no changes in the conformational status of TMH3/TMH6, keeping the ionic lock intact.…”

Section: Ionic Lock and Toggle Switchmentioning

confidence: 99%

GPR6 Structural Insights: Homology Model Construction and Docking Studies

et al. 2020

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GPR6 is an orphan G protein-coupled receptor that has been associated with the cannabinoid family because of its recognition of a sub-set of cannabinoid ligands. The high abundance of GPR6 in the central nervous system, along with high constitutive activity and a link to several neurodegenerative diseases make GPR6 a promising biological target. In fact, diverse research groups have demonstrated that GPR6 represents a possible target for the treatment of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Several patents have claimed the use of a wide range of pyrazine derivatives as GPR6 inverse agonists for the treatment of Parkinson’s disease symptoms and other dyskinesia syndromes. However, the full pharmacological importance of GPR6 has not yet been fully explored due to the lack of high potency, readily available ligands targeting GPR6. The long-term goal of the present study is to develop such ligands. In this paper, we describe our initial steps towards this goal. A human GPR6 homology model was constructed using a suite of computational techniques. This model permitted the identification of unique GPR6 structural features and the exploration of the GPR6 binding crevice. A subset of patented pyrazine analogs were docked in the resultant GPR6 inactive state model to validate the model, rationalize the structure-activity relationships from the reported patents and identify the key residues in the binding crevice for ligand recognition. We will take this structural knowledge into the next phase of GPR6 project, in which scaffold hopping will be used to design new GPR6 ligands.

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Methods for the Development of In Silico GPCR Models

Cited by 17 publications

References 112 publications

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

GPR6 Structural Insights: Homology Model Construction and Docking Studies

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