Binding Mechanism and Synergetic Effects of Xanthone Derivatives as Noncompetitive 伪-Glucosidase Inhibitors: A Theoretical and Experimental Study

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• 作者：Yan Liu ; Lin Ma ; Wen-Hua Chen ; Hwangseo Park ; Zhuofeng Ke ; Bo Wang
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：October 31, 2013
• 年：2013
• 卷：117
• 期：43
• 页码：13464-13471
• 全文大小：553K
• 年卷期：v.117,no.43(October 31, 2013)
• ISSN：1520-5207

文摘

Newly emerged xanthone derivatives have attracted considerable interests as a novel class of potent 伪-glucosidase inhibitors. To provide insights into the inhibitory and binding mechanisms of xanthone-based inhibitors toward 伪-glucosidase, we carried out experimental and theoretical studies on two typical xanthone derivatives, i.e., 1,3,7-trihydroxyxanthone and 1,3-dihydroxybenzoxanthone. The results indicate that these two xanthone derivatives belong to noncompetitive inhibitors and induce a loss in the 伪-helix content of the secondary structure of 伪-glucosidase. Docking simulation revealed the existence of multiple binding modes, in which polyhydroxyl groups and expanded aromatic rings acted as two key pharmacophores to form H-bonding and 蟺鈥撓€ stacking interactions with 伪-glucosidase. The fact that 1,3,7-tridroxyxanthone and 1,3-dihydroxybenzoxanthone exhibited significant synergetic inhibition to 伪-glucosidase strongly suggests that both xanthone derivatives simultaneously bind to the distinct noncompetitive sites of yeast鈥檚 伪-glucosidase. On the basis of the plausible binding clues, synergetic inhibition can be developed to be a promising strategy to achieve enhanced inhibitory activities.