Homology modeling of the human 5-HT1A, 5-HT 2A, D1, and D2 receptors: model refinement with molecular dynamics simulations and docking evaluation.

Journal of Molecular Modeling
Beow Keat YapStephen W Doughty

Abstract

5-HT(1A) serotonin and D1 dopamine receptor agonists have been postulated to be able to improve negative and cognitive impairment symptoms of schizophrenia, while partial agonists and antagonists of the D2 and 5-HT(2A) receptors have been reported to be effective in reducing positive symptoms. There is therefore a need for well-defined homology models for the design of more selective antipsychotic agents, since no three-dimensional (3D) crystal structures of these receptors are currently available. In this study, homology models were built based on the high-resolution crystal structure of the β(2)-adrenergic receptor (2RH1) and further refined via molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer system with the GROMOS96 53A6 united atom force field. Docking evaluations with representative agonists and antagonists using AutoDock 4.2 revealed binding modes in agreement with experimentally determined site-directed mutagenesis data and significant correlations between the computed and experimental pK (i) values. The models are also able to distinguish between antipsychotic agents with different selectivities and binding affinities for the four receptor...Continue Reading

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Citations

Mar 19, 2014·Journal of Molecular Graphics & Modelling·Sek Peng ChinStephen W Doughty
Oct 9, 2012·Chemical Biology & Drug Design·Vani MunusamyLip Yong Chung
Sep 7, 2016·European Journal of Medicinal Chemistry·Marco TutoneViviana De Caro
May 13, 2014·Journal of Chemical Information and Modeling·Krzysztof RatajAndrzej J Bojarski
Mar 5, 2014·Journal of Molecular Recognition : JMR·Jeyachandran SivakamavalliBaskaralingam Vaseeharan
Mar 27, 2018·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Agnieszka A KaczorDariusz Matosiuk
Jul 5, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Feng LinYan Li
Oct 15, 2021·Journal of Chemical Information and Modeling·Yunshuo ZhaoJiangfeng Du
Sep 10, 2020·Current Topics in Medicinal Chemistry·Shome S Bhunia, Anil K Saxena

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