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Binding mode analyses and pharmacophore model development for sulfonamide chalcone derivatives, a new class of α-glucosidase inhibitors   
摘  要:   Sulfonamide chalcone derivatives are a new class of non-saccharide compounds that effectively inhibit glucosidases which are the major targets in the treatment of Type 2 diabetes and HIVinfection. Our aim is to explore their binding mode of interaction at the active site by comparing with the sugar derivatives and to develop a pharmacophore model which would represent the critical features responsible for a-glucosidase inhibitory activity.The homology modeled structure ofSaccharomyces cerevisiae a-glucosidasewasbuilt and used formolecular dockingof non-sugar/sugar derivatives. The validated docking results projected the crucial role of NH group in the binding of sugar/non-sugar derivatives to the active site. Ligplot analyses revealed that Tyr71, and Phe177 form hydrophobic interactions with sugar/non-sugar derivatives by holding the terminal glycosidic ring mimics. Molecular dynamic (MD) simulation studies were performed for protein alone and with chalcone derivative to prove its binding mechanism as shown by docking/Ligplot results. It would also help to substantiate the homology modeled structure stability. With the knowledge of the crucial interactions between ligand and protein from docking and MD simulation studies, features for pharmacophore model development were chosen. TheCATALYST/HipHop was used to generate afivefeatured pharmacophore model with a training set offivenon-sugar derivatives. As validation, all the crucial features of the model were perfectly mapped onto the 3D structures of the sugar derivatives as well as the newly tested non-sugar derivatives. Thus, it can be useful in virtual screening for finding new non-sugar derivatives as a-glucosidase inhibitors.
发  表:   Journal of Molecular Graphics and Modelling  2008

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