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- Title
Comparison of Dynamics of Extracellular Accesses to the β<sub>1</sub> and β<sub>2</sub> Adrenoceptors Binding Sites Uncovers the Potential of Kinetic Basis of Antagonist Selectivity.
- Authors
Selvam, Balaji; Wereszczynski, Jeff; Tikhonova, Irina G.
- Abstract
From the molecular mechanism of antagonist unbinding in the β1 and β2 adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of β1-selective Esmolol and β2-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the β1 adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the β2 adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the β1 adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the β2 adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface.
- Subjects
MOLECULAR dynamics; BETA adrenoceptors; BINDING sites; PHARMACOKINETICS; LIGANDS (Biochemistry); DRUG design; G protein coupled receptors
- Publication
Chemical Biology & Drug Design, 2012, Vol 80, Issue 2, p215
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2012.01390.x