{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:58:03Z","timestamp":1787237883243,"version":"build-2736575974"},"reference-count":85,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T00:00:00Z","timestamp":1581033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["KO5 DA021358"],"award-info":[{"award-number":["KO5 DA021358"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2019s disease, Alzheimer\u2019s disease, and Huntington\u2019s disease. Several patents have claimed the use of a wide range of pyrazine derivatives as GPR6 inverse agonists for the treatment of Parkinson\u2019s 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.<\/jats:p>","DOI":"10.3390\/molecules25030725","type":"journal-article","created":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T11:50:28Z","timestamp":1581076228000},"page":"725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["GPR6 Structural Insights: Homology Model Construction and Docking Studies"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-5370","authenticated-orcid":false,"given":"Israa H.","family":"Isawi","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6209-8600","authenticated-orcid":false,"given":"Paula","family":"Morales","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Medica (IQM-CSIC), C\/Juan de la Cierva 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noori","family":"Sotudeh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, The State University of New York at Buffalo, Buffalo, NY 14260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dow P.","family":"Hurst","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane L.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia H.","family":"Reggio","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2016","journal-title":"Nat. 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