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Abstract #26670 Published in IGR 12-3
Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor
Novoseletsky VN; Pyrkov TV; Efremov RGSAR and QSAR in Environmental Research 2010; 21: 37-55
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.
V. N. Novoseletsky. M.M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, 117997 GSP, Moscow V-437, Russian Federation. valeryns@nmr.ru
Classification:
3.8 Pharmacology (Part of: 3 Laboratory methods)
11.3.4 Betablocker (Part of: 11 Medical treatment > 11.3 Adrenergic drugs)
