Calderón, Jacqueline C; Ibrahim, Passainte; Gobbo, Dorothea; Gervasio, Francesco Luigi; Clark, Timothy; (2024) Determinants of Neutral Antagonism and Inverse Agonism in the β2-Adrenergic Receptor. Journal of Chemical Information and Modeling , 64 (6) pp. 2045-2057. 10.1021/acs.jcim.3c01763.

Text ADRB2_antagonism_final.pdf - Accepted Version Access restricted to UCL open access staff until 7 March 2025. Download (7MB)

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.

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