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

被引：6

作者：

Novoseletsky, V. N. ^{[1
]}

Pyrkov, T. V. ^{[1
]}

Efremov, R. G. ^{[1
]}

机构：

[1] Russian Acad Sci, MM Shemyakin & Yu A Ovchinnikov Inst Bioorgan Che, Moscow 117997, Russia

来源：

SAR AND QSAR IN ENVIRONMENTAL RESEARCH | 2010年 / 21卷 / 1-2期

基金：

俄罗斯基础研究基金会;

关键词：

protein-ligand interactions; molecular hydrophobicity potential; G-protein-coupled receptors; beta-adrenoceptor; BETA-ADRENERGIC-RECEPTOR; PROTEIN-COUPLED RECEPTOR; ADENYLATE-CYCLASE SYSTEM; BETA(2)-ADRENERGIC RECEPTOR; THERMODYNAMIC PROPERTIES; MOLECULAR LIPOPHILICITY; CONFORMATIONAL-CHANGES; AGONIST INTERACTIONS; GENETIC ALGORITHM; CRYSTAL-STRUCTURE;

D O I：

10.1080/10629360903560637

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 (r2 0.8) with experimental data.

引用

页码：37 / 55

页数：19

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