Exploring the structural basis and atomistic binding mechanistic of the selective antagonist blockade at D3 dopamine receptor over D2 dopamine receptor.

Abstract

More recently, there has been a paradigm shift toward selective drug targeting in the treatment of neurological disorders, including drug addiction, schizophrenia, and Parkinson's disease mediated by the different dopamine receptor subtypes. Antagonists with higher selectivity for D3 dopamine receptor (D3DR) over D2 dopamine receptor (D2DR) have been shown to attenuate drug-seeking behavior and associated side effects compared to non-subtype selective antagonists. However, high conservations among constituent residues of both proteins, particularly at the ligand-binding pockets, remain a challenge to therapeutic drug design. Recent studies have reported the discovery of two small-molecules R-VK4-40 and Y-QA31 which substantially inhibited D3DR with >180-fold selectivity over D2DR. Therefore, in this study, we seek to provide molecular and structural insights into these differential binding mechanistic using meta-analytic computational simulation methods. Findings revealed that R-VK4-40 and Y-QA31 adopted shallow binding modes and were more surface-exposed at D3DR while on the contrary, they exhibited deep hydrophobic pocket binding at D2DR. Also, two non-conserved residues; Tyr361.39 and Ser18245.51 were identified in D3DR, based on their crucial roles and contributions to the selective binding of R-VK4-40 and Y-QA31. 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 D2 -like dopamine family receptor subtype with improved potency and selectivity.

• Authors: Patrick Appiah-Kubi, Fisayo Andrew Olotu, Mahmoud E S Soliman
• Journal: Journal of molecular recognition : JMR (J Mol Recognit) Vol. 34 Issue 5 Pg. e2885 (05 2021) ISSN: 1099-1352 [Electronic] England
• PMID: 33401335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons Ltd.

Chemical References

• Benzothiazoles
• DRD2 protein, human
• DRD3 protein, human
• Indoles
• Piperazines
• R-VK4-40
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Y-QA31

Topics

• Benzothiazoles (chemistry, pharmacology)
• Binding Sites
• Humans
• Hydrophobic and Hydrophilic Interactions
• Indoles (chemistry, pharmacology)
• Models, Molecular
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Molecular Structure
• Piperazines (chemistry, pharmacology)
• Protein Binding
• Protein Conformation
• Receptors, Dopamine D2 (agonists, chemistry, metabolism)
• Receptors, Dopamine D3 (agonists, chemistry, metabolism)
• Structure-Activity Relationship