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

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
DOI: 10.1002/cmdc.201500599 Publication Date: 2016-03-19T07:23:21Z
ABSTRACT
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.
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