Structure‐Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics

Structure‐based virtual screening using a D₂ receptor homology model was performed to identify dopamine D₂ receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D₂ ligands were identified (47.6 % success rate, among them D₂ receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5‐HT_2A receptors. The affinity (K_i values) of the compounds ranged from 58 nm to about 24 μm . Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D₂ receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D₂ pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20‐fold binding selectivity for the D₂ receptor over the D₃ receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.