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

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.

Withdrawal Notice: Elucidating the Disparate Inhibitory Mechanisms of Novel 1-Heteroaryl-1,3-Propanediamine Derivatives and Maraviroc towards C-C Chemokine Receptor 5: Insights for Structural Modifications in HIV-1 Drug Discovery

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Probing Binding Landscapes and Molecular Recognition Mechanisms of Atypical Antipsychotic Drugs towards the Selective Targeting of D2 Dopamine Receptor.

Dopamine receptors constitute a unique class of G-protein coupled receptors that mediate the activities of dopamine, a neurotransmitter implicated in diverse neurological diseases when dysregulated. Over the years, antipsychotic drugs have been primarily directed towards D2 dopamine receptor (DRD2) while associable adverse effects have been centred on non-selective targeting. The recent crystal structure of DRD2 in complex with atypical antipsychotic could further aid the structure-based design of highly DRD2-selective antipsychotics. Therefore, in this study, we comprehensively investigate the molecular recognition and differential binding landscapes of class-I and II DRD2 atypical antipsychotics, using membrane-bilayer molecular dynamics simulation and binding free energy techniques. Findings revealed that selected class-I antipsychotics exhibited binding dynamics and poses dissimilar to the class-II types with different interactive mechanisms at the binding cavity of DRD2. More interestingly, the class-II drugs established a highly coordinated binding at the DRD2 active site with a pertinent and recurrent involvement of Asp114 via strong hydrogen interactions. Furthermore, while these compounds exert distinct effects on DRD2 structure, findings revealed that the class-II types favourably engaged the deep hydrophobic pocket of DRD2 compared to the class-I drugs. We speculate that these findings will be fundamental to the discovery of highly selective DRD2 antipsychotics.