Molecular modeling and docking study on dopamine D-2-like and serotonin 5-HT2A receptors

摘要

Psychiatric disorders, such as schizophrenia, bipolar disorder and major depression, are paid more and more attention by human due to their upward tendency in modern society. D-2-like and 5-HT2A receptors have been proposed as targets of antipsychotic drugs. Atypical antipsychotic drugs have been deemed to improve the treatment of positive, negative and extrapyramidal symptoms. Unfortunately, no experimental structures for these receptors are available except D-3 receptor (D3R). Therefore, it is necessary to construct structures of D-2-like and 5-HT2A receptors to investigate the interaction between these receptors and their antagonists. Accordingly, homology models of dopamine D-2, D-3, D-4 and serotonin 5-HT2A receptors have been built on the high-resolution crystal structure of the beta(2)-adrenergic receptor, and refined by molecular dynamics simulations. The backbone root-mean-square deviation (RMSD) of D3R model relative to crystal structure is 1.3 angstrom, which proves the reliability of homology modeling. Docking studies reveal that the binding modes of four homology models and their antagonists are consistent with experimental site-directed mutagenesis data. The calculated pK(1) values agree well with the experimental pK(i) ones. Antagonists with linear structures such as butyrophenones and benzisoxazolyl piperidines are easily docked into D-2-like and 5-HT2A receptors. Polycyclic aromatic compounds have weaker affinity with four receptors. Homology models of D-2-like and 5-HT2A receptors will be helpful for predicting the affinity of novel ligands, and could be used as three-dimensional (3D) templates for antipsychotic virtual screening and further drug discovery. (C) 2015 Elsevier Inc. All rights reserved.