Ligand and Structure Based Models for the Identification of Beta 2 Adrenergic Receptor Antagonists

Author(s): Jayadev Joshi, Manali Dimri, Subhajit Ghosh, Nitisha Shrivastava, Rina Chakraborti, Neeta Sehgal, Jharna Ray, Indracanti Prem Kumar

Journal Name: Current Computer-Aided Drug Design

Volume 11 , Issue 3 , 2015

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Ligand bound beta 2 adrenergic receptor (β2AR) crystal structures are in use for screening of compound libraries for identifying inducers and blockers. However, in case of G protein coupled receptors (GPCR), docking and binding energy (BE) calculations are not enough to discriminate agonist and antagonists. Absence of a reliable model for discriminating β2AR antagonist is still a major hurdle. Docking of known antagonists and agonists into activated and ground state β2AR revealed several key intermolecular interactions and H-bonding patterns, which in combination, emerged as a model for prediction of antagonists. Present study identifies an alternative binding orientation, within the binding pocket, for blockers and a minimum grid size to lessen the false positive predictions. Cluster analysis revealed structural variability among the antagonists and a conserved pattern in case of agonists. A combination of docking and structure activity relationship (SAR) model reliably discriminated antagonists. Based on key intermolecular interactions, a set of agonists and antagonists useful to SAR, quantitative structure activity relationship (QSAR) and pharmacophore modeling, has also been proposed for identifying antagonists.

Keywords: β2AR, beta blocker, cluster analysis, docking, GPCR. SAR, screening.

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Article Details

Year: 2015
Page: [222 - 236]
Pages: 15
DOI: 10.2174/1573409911666150812130420
Price: $65

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PDF: 53
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