Molecular Dynamics Simulations Reveal Fundamental Role of Water As Factor Determining Affinity of Binding of β-Blocker Nebivolol to β₂-Adrenergic Receptor

Abstract

The beta-adrenergic antagonists (beta-blockers) constitute a class of drugs that have well-established roles in treatments of various cardiovascular diseases. Despite a 50 year history, there are two clinically important subtypes of beta-adrenergic receptors (betaARs) called beta(1)AR and beta(2)AR that still are promising drug targets. Our study maps the interactions between nebivolol-one of the most efficient beta-blocking agents-and the beta(2)-adrenergic receptor by simulating two optical isomers of nebivolol: ssss-nebivolol and srrr-nebivolol. The srrr-configuration binds preferentially to beta(1)AR and beta(2)AR. The ssss-form has much lower binding affinity to both of them. Our work indicates that water is a very important component of the binding site of the beta(2)AR receptor. We found that the higher stereoselectivity of the srrr-configuration is due to interactions with water molecules, which extensively hydrate the binding site of beta(2)AR. By lowering the energy of binding, water enhanced the affinity of the srrr-form to beta(2)AR. We also address the problem of beta(1)AR/beta(2)AR selectivity. At higher concentrations, all beta-blocking agents lose their specificity and bind nonselectively, causing many adverse effects. Our simulations indicate that PHE194, TYR308, and ILE309 of the beta(2)AR and the corresponding residues of the beta(1)AR receptor may be important determinants of beta(1)AR versus beta(2)AR selectivity.

Lipid Simulations: A Perspective on Lipids in Action

“…3) (Kaszuba et al 2010). b-ARs belong to the family of G-protein coupled receptors (GPCRs) that constitute about 80% of the known receptors for neurotransmitters, hormones, and neuromodulators, and about 5% of the genes in eukaryotic organisms (Vigh et al 2005).…”

“…Very recently, atomistic molecular dynamics simulations were used to unravel the issue of nebivolol selectivity toward one of the receptor's subtypes, as well as to understand its stereo-specificity (Kaszuba et al 2010). Simulations clearly showed that the srrr-form interacts more favorably with the receptor, demonstrating the capacity of atomistic MD simulations for determining stereo-specificity.…”

“…One of Figure 3. View of the binding pocket of b2-AR occupied by a nebivolol molecule (Kaszuba et al 2010). The left panel shows water molecules present in the pocket, whereas the right panel shows protein residues involved in direct interaction with nebivolol.…”

Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β2adrenoceptor for the selective design of agonists or antagonists

“…[48 -50] In this study, there was a close proximity between N293 and Y308 in the activeagonist Gb 2 AR models, compared with the ligand-induced proximity observed in the inactive -basal forms (Supplementary material, available via the article webpage, Figure 4). The latter condition has been associated with a 'post-ligand binding' stable state, [51] or with a rearrangement of a stereoselective switch. [52] We built 3D stereoisomers of the test ligands in order to observe possible differences in their contact with residues on the Gb 2 AR models.…”

“…Simulation 1249 modifications have been tested to improve the accuracy of theoretical tools, including the vacuum structural optimisation of receptors, [41] the structural refinement of receptor membrane embedding by using MD, [47,51] the use of flexible ligands [41] and the addition of other factors, such as the influence of lateral chains and/or selected residues in the 7TMRs. [8,45,52] The modification of theoretical methodology in these ways has resulted in an apparent improvement in the scoring function applied to a specific 7TMR, but has not provided a general method that is usable on several 7TMRs, as evidenced by the inability to achieve an adequate score function.…”