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Computational insights into ligand–induced G protein and β-arrestin signaling of the dopamine D1 receptor

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Abstract

The dopamine D1 receptor (D1R), is a class A G protein coupled-receptor (GPCR) which has been a promising drug target for psychiatric and neurological disorders such as Parkinson’s disease (PD). Previous studies have suggested that therapeutic effects can be realized by targeting the β-arrestin signaling pathway of dopamine receptors, while overactivation of the G protein-dependent pathways leads to side effects, such as dyskinesias. Therefore, it is highly desirable to develop a D1R ligand that selectively regulates the β-arrestin pathway. Currently, most D1R agonists are signaling-balanced and stimulate both G protein and β-arrestin pathways, with a few reports of G protein biased ligands. However, identification and characterization of β-arrestin biased D1R agonists has been a challenge thus far. In this study, we implemented Gaussian accelerated molecular dynamics (GaMD) simulations to provide valuable computational insights into the possible underlying molecular mechanism of the different signaling properties of two catechol and two non-catechol D1R agonists that are either G protein biased or signaling-balanced. Dynamic network analysis further identified critical residues in the allosteric signaling network of D1R for each ligand at different conformational or binding states. Some of these residues are crucial for G protein or arrestin signals of GPCRs based on previous studies. Finally, we provided a molecular design strategy which can be utilized by medicinal chemists to develop potential β-arrestin biased D1R ligands. The proposed hypotheses are experimentally testable and can guide the development of safer and more effective medications for a variety of CNS disorders.

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Abbreviations

cMD:

Conventional MD

D1R:

Dopamine D1 receptor

GaMD:

Gaussian accelerated molecular dynamics

GPCR:

G protein-coupled receptor

MD:

Molecular dynamics

SFSR:

Structure-functional selectivity relationships

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Acknowledgements

We would like to thank Dr. Alican Gulsevin at Vanderbilt University for the helpful suggestions in this project.

Funding

H.L. was supported by a fellowship (Finish-Line Award) from University of Florida.

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Authors and Affiliations

  1. Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA

    Haoxi Li & Nicole Horenstein

  2. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA

    Nikhil M. Urs

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  1. Haoxi Li
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  2. Nikhil M. Urs
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  3. Nicole Horenstein
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Contributions

HL designed and performed the study, analyzed the data, and wrote the manuscript. NMU wrote the manuscript. NH designed the study and wrote the manuscript.

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Correspondence to Nicole Horenstein.

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Li, H., Urs, N.M. & Horenstein, N. Computational insights into ligand–induced G protein and β-arrestin signaling of the dopamine D1 receptor. J Comput Aided Mol Des 37, 227–244 (2023). https://doi.org/10.1007/s10822-023-00503-7

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  • DOI: https://doi.org/10.1007/s10822-023-00503-7

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