Molecular dynamics simulations reveal fundamental role of water as factor determining affinity of binding of β-blocker nebivolol to β2-adrenergic receptor

The ß-adrenergic antagonists (ß-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 ß-adrenergic receptors (ßARs) called ß1AR and ß2AR that still are promising drug targets. Our study maps the interactions between nebivolol¿one of the most efficient ß-blocking agents¿and the ß2-adrenergic receptor by simulating two optical isomers of nebivolol: ssss-nebivolol and srrr-nebivolol. The srrr-configuration binds preferentially to ß1AR and ß2AR. 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 ß2AR 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 ß2AR. By lowering the energy of binding, water enhanced the affinity of the srrr-form to ß2AR. We also address the problem of ß1AR/ß2AR selectivity. At higher concentrations, all ß-blocking agents lose their specificity and bind nonselectively, causing many adverse effects. Our simulations indicate that PHE194, TYR308, and ILE309 of the ß2AR and the corresponding residues of the ß1AR receptor may be important determinants of ß1AR versus ß2AR selectivity.