Beta blocker Nebivolol (srrr form) in the binding pocket of beta-2 receptor

Beta-adrenergic receptors have many vital physiological functions: for example, beta-1 receptors are important for the contractility of heart muscle, beta-2 for lungs and beta-3 for adipose tissue. Due to their importance, beta receptors are natural targets for drug development. beta-1 blockers, atenolol, are used treatment of cardiac arrythmias and congestive heart disease. Beta-2, as it is important in lungs, is a target for asthma treatment. Salbutamol being one of the most common ones. Nebivolol is a fairly new beta blocker. It binds selectively to beta-1 receptors and it is used in treatment of hypertension. Nebivolol is the most selective beta-1 blocker. The origin of selectivity is, however, poorly understood. Our aim here is to investigate the molecular origin of this selectivity. This was done by combining large scale molecular dynamics and molecular docking studies using the beta-2 receptor with nebivolol. Our study shows that water has a very important role determining binding affinity. This is, to our knowledge, the first demonstration of the importance of water in beta-blocker binding. We used two optical isomers of nebivolol, the so-called ssss- and srrr-forms and the interactions with water turned out to be the decisive factor in the better binding of the srrr-form. The movies shows a nebivolol molecule (red) in the binding pocket of a beta-2 receptor. The receptor is embedded in a lipid membrane (shown in green) and we have zoomed into the region of the nebivolol-receptor interaction. The slow motion of hydrating water (purple) is very clear. Reference: Molecular docking, multiple sequence alignment and atomistic molecular dynamics simulations reveal residues associated with selective binding of beta-blockers to human beta-1 and beta-2-adrenergic receptors, K. Kaszuba, T. Rog, K. Bryl, I. Vattulainen, and M. Karttunen, J. Phys. Chem. B 114, 8374-8366 (2010) http://dx.doi.org/10.1021/jp909971f