GPR6 Structural Insights: Homology Model Construction and Docking Studies

Abstract

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.

Illuminating the Druggable Genome through Patent Bioactivity Data

“…Some endogenous ligands have been proposed for this receptor but due to inconsistencies among assays, it is categorized as orphan by the International Union of Basic and Clinical Pharmacology (IUPHAR) 35 . The physiological role of GPR6 has not been fully elucidated but it has been suggested that it could be involved in several diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease 36 and schizophrenia.…”

Glycine: The Smallest Anti-Inflammatory Micronutrient

“…GPRC6 is a 362 amino acid [58] orphan receptor coupled to a stimulatory Gα subunit (Gαs). It has been associated with the cannabinoid family, class A (similar to rhodopsin) [58][59][60], which phylogenetically belongs to the melanocortin/endothelial differentia-tion/ cannabinoid/adenosine (MECA) [61]. It has been shown in oocytes that GPR6 can be activated by glycine, this being a small neutral aliphatic L-α-amino acid that could act as an endogenous agonist in concentrations of 100 µM [62].…”

Endocannabinoid signaling pathways: beyond CB1R and CB2R

“…There are no reported X‐ray structures, however, SWISS‐Model site hosts a model (6pt0.1.A) based on the cryo‐EM structure of human cannabinoid receptor 2 ‐G i protein in complex with agonist WIN 55,212‐2 (28.1% sequence homology, PDB entry 6PTO) to serve as a working template (Waterhouse et al 2018). Isawi et al (2020) describe a model of their own based on the S1P1 receptor. Posttranslational modifications are predicted, but none have been confirmed experimentally (Table S1).…”