Determinants of Neutral Antagonism and Inverse Agonism in the β2-Adrenergic Receptor

Calderón Reyes J, Ibrahim P, Gobbo D, Gervasio FL, Clark T (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Journal of Chemical Information and Modeling American Chemical Society

Book Volume: 64

Pages Range: 2045-2057

Journal Issue: 6

DOI: 10.1021/acs.jcim.3c01763

Abstract

Free-energy profiles for the activation/deactivation of the β2-adrenergic receptor (ADRB2) with neutral antagonist and inverse agonist ligands have been determined with well-tempered multiple-walker (MW) metadynamics simulations. The inverse agonists carazolol and ICI118551 clearly favor single inactive conformational minima in both the binary and ternary ligand-receptor-G-protein complexes, in accord with the inverse-agonist activity of the ligands. The behavior of neutral antagonists is more complex, as they seem also to affect the recruitment of the G-protein. The results are analyzed in terms of the conformational states of the well-known microswitches that have been proposed as indicators of receptor activity.

Authors with CRIS profile

Jacqueline Calderón Reyes Computer-Chemie-Centrum Timothy Clark Computer-Chemie-Centrum

Involved external institutions

University of Geneva / Université de Genève (UNIGE) CH Switzerland (CH) Universität Leipzig DE Germany (DE)

How to cite

APA:

Calderón Reyes, J., Ibrahim, P., Gobbo, D., Gervasio, F.L., & Clark, T. (2024). Determinants of Neutral Antagonism and Inverse Agonism in the β2-Adrenergic Receptor. Journal of Chemical Information and Modeling, 64(6), 2045-2057. https://doi.org/10.1021/acs.jcim.3c01763

MLA:

Calderón Reyes, Jacqueline, et al. "Determinants of Neutral Antagonism and Inverse Agonism in the β2-Adrenergic Receptor." Journal of Chemical Information and Modeling 64.6 (2024): 2045-2057.

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