Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor

Abstract

The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists (‘beta-blockers’) thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor–ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r ²∼ 0.8) with experimental data.

Keywords:

• protein–ligand interactions
• molecular hydrophobicity potential
• G-protein-coupled receptors
• beta-adrenoceptor

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (grants Nos 07-04-01514-a, 09-04-13813-ofi-a), by the RAS Programme (MCB and ‘Basic fundamental research of nanotechnologies and nanomaterials’) and by the grant SS-4728.2006.