Journal
CURRENT COMPUTER-AIDED DRUG DESIGN
Volume 11, Issue 3, Pages 222-236Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1573409911666150812130420
Keywords
beta 2AR; beta blocker; cluster analysis; docking; GPCR. SAR; screening
Funding
- INMAS
- DRDO
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Ligand bound beta 2 adrenergic receptor (beta 2AR) 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 beta 2AR antagonist is still a major hurdle. Docking of known antagonists and agonists into activated and ground state beta 2AR 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.
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