Identification of Novel Dopamine D₂ Receptor Ligands-A Combined In Silico/In Vitro Approach

Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D₂ (D₂R) has been shown to be involved in central nervous system diseases. While different D₂R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D₂R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D₂R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D₂R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D₂R. This workflow successfully identified six novel D₂R ligands exerting micro- to nanomolar (most active compound K_I = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D₂R-associated pathologies.