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Antagonists with higher selectivity for D<jats:sub>3<\/jats:sub> dopamine receptor (D3DR) over D<jats:sub>2<\/jats:sub> dopamine receptor (D2DR) have been shown to attenuate drug\u2010seeking behavior and associated side effects compared to non\u2010subtype selective antagonists. However, high conservations among constituent residues of both proteins, particularly at the ligand\u2010binding pockets, remain a challenge to therapeutic drug design. Recent studies have reported the discovery of two small\u2010molecules R\u2010VK4\u201040 and Y\u2010QA31 which substantially inhibited D3DR with &gt;180\u2010fold selectivity over D2DR. Therefore, in this study, we seek to provide molecular and structural insights into these differential binding mechanistic using meta\u2010analytic computational simulation methods. Findings revealed that R\u2010VK4\u201040 and Y\u2010QA31 adopted shallow binding modes and were more surface\u2010exposed at D3DR while on the contrary, they exhibited deep hydrophobic pocket binding at D2DR. Also, two non\u2010conserved residues; Tyr36<jats:sup>1.39<\/jats:sup> and Ser182<jats:sup>45.51<\/jats:sup> were identified in D3DR, based on their crucial roles and contributions to the selective binding of R\u2010VK4\u201040 and Y\u2010QA31. Importantly, both antagonists exhibited high affinities in complex with D3DR compared to D2DR, while van der Waals energies contributed majorly to their binding and stability. Structural analyses also revealed the distinct stabilizing effects of both compounds on D3DR secondary architecture relative to D2DR. Therefore, findings herein pinpointed the origin and mechanistic of selectivity of the compounds, which may assist in the rational design of potential small molecules of the D<jats:sub>2<\/jats:sub>\u2010like dopamine family receptor subtype with improved potency and selectivity.<\/jats:p>","DOI":"10.1002\/jmr.2885","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T22:04:08Z","timestamp":1609970648000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring the structural basis and atomistic binding mechanistic of the selective antagonist blockade at <scp>D<sub>3<\/sub><\/scp> dopamine receptor over <scp>D<sub>2<\/sub><\/scp> dopamine receptor"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5904-3051","authenticated-orcid":false,"given":"Patrick","family":"Appiah\u2010Kubi","sequence":"first","affiliation":[{"name":"Molecular Bio\u2010computation and Drug Design Laboratory, School of Health Sciences University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fisayo Andrew","family":"Olotu","sequence":"additional","affiliation":[{"name":"Molecular Bio\u2010computation and Drug Design Laboratory, School of Health Sciences University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud E. 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