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

被引：1
|
作者：
Calderon, Jacqueline C. [1 ]
Ibrahim, Passainte [2 ]
Gobbo, Dorothea [3 ,4 ]
Gervasio, Francesco Luigi [3 ,4 ,5 ,6 ]
Clark, Timothy [1 ]
机构：
[1] Friedrich Alexander Univ Erlangen Nuernberg, Comp Chem Ctr, Dept Chem & Pharm, D-91052 Erlangen, Germany
[2] Univ Leipzig, Inst Med Phys & Biophys, Fac Med, D-04107 Leipzig, Germany
[3] Univ Geneva, Pharmaceut Sci, CH-1206 Geneva, Switzerland
[4] Inst Pharmaceut Sci Western Switzerland, CH-1206 Geneva, Switzerland
[5] UCL, Chem Dept, London WC1H 0AJ, England
[6] Swiss Bioinformat Inst, Geneva, Switzerland
来源：
JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2024年 / 64卷 / 06期
基金：
瑞士国家科学基金会;
关键词：
PROTEIN-COUPLED RECEPTORS; BETA(2) ADRENERGIC-RECEPTOR; ENERGY LANDSCAPES; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; LIGAND EFFICACY; GS-PROTEIN; ACTIVATION; DYNAMICS; BINDING;
D O I：
10.1021/acs.jcim.3c01763
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Free-energy profiles for the activation/deactivation of the beta(2)-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.
引用
收藏
页码：2045 / 2057
页数：13
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