Identification of Novel Dopamine D(2) 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 D(2) (D(2)R) has been shown to be involved in central nervous system diseases. While different D(2)R-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 D(2)R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D(2)R 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 D(2)R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D(2)R. This workflow successfully identified six novel D(2)R 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 D(2)R-associated pathologies.