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

The β-adrenergic antagonists (β-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 β-adrenergic receptors (βARs) called β1AR and β2AR that still are promising drug targets. Our study maps the interactions between nebivolol―one of the most efficient β-blocking agents―and the β2-adrenergic receptor by simulating two optical isomers of nebivolol: ssss-nebivolol and srrr-nebivolol. The srrr-configuration binds preferentially to β1AR and β2AR. 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 β2AR 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 β2AR. By lowering the energy of binding, water enhanced the affinity of the srrr-form to β2AR. We also address the problem of β1AR/β2AR selectivity. At higher concentrations, all β-blocking agents lose their specificity and bind nonselectively, causing many adverse effects. Our simulations indicate that PHE194, TYR308, and ILE309 of the β2AR and the corresponding residues of the β1AR receptor may be important determinants of β1AR versus β2AR selectivity.