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.