Molecular dynamics simulation of biased agonists at the dopamine D2 receptor suggests the mechanism of receptor functional selectivity

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.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Based on comparison of the available active and inactive GPCR structures, the most significant rearrangements occur in the intracellular site, especially in the TM6 region [82,83] and recently 13 state-specific conserved inter-TM interactions were identified [84]. It is possible to stimulate different intracellular signaling pathways independently via biased agonists [85,86] through a single GPCR. Many GPCRs possess secondary (allosteric) binding sites that influence intracellular signaling in distinct manners.…”

Binding Interactions of Ergotamine and Dihydroergotamine to 5-Hydroxytryptamine Receptor 1B (5-HT1b) Using Molecular Dynamics Simulations and Dynamic Network Analysis

“…32 MD simulation was used by Liu and coworkers to characterize the interactions between high-affinity GPCR chemokine receptor 1 and interleukin-8. 33 We have also used MD simulation in our previous work to probe the binding of biased agonists to the D2 dopamine receptor, 34 the interaction between morphine and IBNtxA in complex with the μ-opioid receptor, 35 and described the antagonist activity of fexofenadine to the histamine (H1) receptor. 36 Specific to the 5-hydroxytryptamine receptor, Sylte et al 37,38 and Seeber et al 39 have successfully probed the ligand-induced different conformational states of the 5-HT 1A receptor using comparative MD simulations.…”

Newly Developed Dopamine D3Receptor Antagonists,R-VK4-40 andR-VK4-116, Do Not Potentiate Cardiovascular Effects of Cocaine or Oxycodone in Rats

“…A final possibility is that the structural differences between these compounds (see Fig. 1) preferentially activate different intracellular signaling pathways in a biased manner, as has been reported previously for opioid receptor agonists (Schmid et al, 2017) and recently for dopamine receptor ligands (Weïwer et al, 2018;Montgomery et al, 2019). As one example, cariprazine, a D 3 R-preferring partial agonist used in the treatment of schizophrenia, may display either antagonist or partial agonist effects depending upon receptor location, G-protein coupling, and dopaminergic tone (Kiss et al, 2010;De Deurwaerdère, 2016).…”