title: 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) approximately 0.8) with experimental data.
authors.affiliation: MM Shemyakin & Yu A Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul Miklukho-Maklaya, Moscow V-437, Russia. valeryns@nmr.ru
authors.forename: V N
authors.initials: VN
authors.lastname: Novoseletsky
authors.forename: T V
authors.initials: TV
authors.lastname: Pyrkov
authors.forename: R G
authors.initials: RG
authors.lastname: Efremov
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D018343:Receptors, Adrenergic, beta-2