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Molecular Dynamics Simulation of Biased Agonists at the Dopamine D2 Receptor Suggests the Mechanism of Receptor Functional Selectivity

Molecular Dynamics Simulation of Biased Agonists at the Dopamine D2 Receptor Suggests the Mechanism of Receptor Functional Selectivity

David Montgomery, Alexandra Campbell, Holli-Joi Sullivan, Chun Wu

J Biomol Struct Dyn. 2019 Aug;37(12):3206-3225.

PMID: 30124143

Abstract:

The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson's disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein-ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling. Communicated by Ramaswamy H. Sarma.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP315698363	MLS1547		315698-36-3	Price

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