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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 29, Number 5
BKCSDE 29(5)
May 20, 2008 

 
Title
Toward the Virtual Screening of α-Glucosidase Inhibitors with the Homology-Modeled Protein Structure
Author
Jung-Hum Park, Sungmin Ko, Hwangseo Park*
Keywords
Docking, Scoring function, Virtual screening, Homology modeling, α-Glucosidase inhibitor
Abstract
Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate mediated diseases. As a method for the discovery of new novel inhibitors of α-glucosidase, we have addressed the performance of the computer-aided drug design protocol involving the homology modeling of α-glucosidase and the structure-based virtual screening with the two docking tools: FlexX and the automated and improved AutoDock implementing the effects of ligand solvation in the scoring function. The homology modeling of α-glucosidase from baker’s yeast provides a high-quality 3-D structure enabling the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands to the extent of 5-fold enhancement of hit rate in database screening when 1% of database coverage is used as a cutoff. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of α- glucosidase through the simultaneous establishment of the multiple hydrogen bond and hydrophobic interactions. The present study demonstrates the usefulness of the automated AutoDock program with the improved scoring function as a docking tool for virtual screening of new α-glucosidase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.
Page
921 - 927
Full Text
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