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Automated in silico modelling and docking of ligands on benzodiazepine binding site of GABAA receptors

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Author(s): Gajanan Vaishnav1*, Kulkarni G. K2and S. Sankar3

Journal: Journal of Pharmacy Research
ISSN 0974-6943

Volume: 4;
Issue: 9;
Start page: 3162;
Date: 2011;
Original page

Keywords: Allosteric Regulation/genetics | Animals | Benzodiazepines/metabolism* | Binding Sites/genetics | Ligands | Models | Molecular | Protein Binding/ genetics | Rats | Receptors | GABA-A/chemistry | Receptors | GABA-A/metabolism* | Structure-Activity Relationship | Fuzzy oil drop model

ABSTRACT
Many antianxiety, sedative and antiepileptic ligands such as benzodiazepines (BZDs) act by allosteric modulation of the GABA(A) receptor via the benzodiazepinebinding site. This increases the affinity of GABA for the receptors. The exact mode of docking of these ligands in the 1,4-benzodiazepine (BZD) recognition sitehas been a subject of recent in-silico docking studies. These studies have utilized previous attempts which have been made to superimpose the structures of allostericmodulators to construct a pharmacophore model for the BZD recognition site or manual editing of homology sequences. However, such models are difficult torelate to receptor structure and tedious to produce. The reproducibility of manual editing is also questionable. In the present study, the X-ray structure of anacetylcholine binding protein from the snail Lymnaea stagnalis and the results from site-directed affinity-labeling studies were used as the basis for modeling of theBZD binding pocket at the a1 / g2 subunit interface. With fully automated homology modeling pipeline SWISS-MODEL and binding pocket for the homology modelwas predicted with fuzzy oil drop Gaussian server. Ligands known to interact with BZD binding site were energy minimized, introduced into the binding pocket andmolecular simulations were carried out to yield a set of binding poses of the BZD ligands in the binding pocket. A fast, easy and reproducible model providing a basisfor the design and selection of GABAA receptor benzodiazepine binding site modulators has been reported in this study. The best docking poses of ligands were foundto be in good confirmation with their reported affinities towards receptor binding site. 55GLN and 114 TYR residues were common in all the best ligand dockingposes in the binding packet.
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