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

• DOI: 10.1002/cmdc.201500599
• Publication Date: 2016-03-19T07:23:21Z
• Authors: Agnieszka A. Kaczor; Andrea G. Silva; María I. Loza; Peter Kolb; Marián Castro; Antti Poso
• Keywords: 0301 basic medicine; Structure-Activity Relationship; 03 medical and health sciences; Dose-Response Relationship, Drug; Molecular Structure; Receptors, Dopamine D2; Drug Evaluation, Preclinical; Humans; Ligands; Antipsychotic Agents

Abstract Structure‐based virtual screening using a D 2 receptor homology model was performed to identify dopamine ligands as potential antipsychotics. From library of 6.5 million compounds, 21 were selected and subjected experimental validation. these compounds tested, ten identified (47.6 % success rate, among them antagonists, expected) that have additional affinity for other receptors in particular 5‐HT 2A receptors. The ( K i values) the ranged from 58 n m about 24 μ . Similarity fragment analysis indicated significant degree structural novelty compounds. We found one antagonist did not protonatable nitrogen atom, which is key element classical pharmacophore necessary interaction with conserved Asp(3.32) residue. This compound exhibited greater than 20‐fold binding selectivity over 3 receptor. provide evidence amide hydrogen atom this forms bond Asp(3.32), determined by tests its derivatives cannot maintain interaction.