Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 117, Issue 43, Pages 13464-13471Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp4067235
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Funding
- National Natural Science Foundation of China [21272290, 21203256]
- Hundred Talent Program of Sun Yat-sen University
- Program for New Century Excellent Talents in University [NCET-11-0920]
- Department of Education of Guangdong Province, China
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Newly emerged xanthone derivatives have attracted considerable interests as a novel class of potent alpha-glucosidase inhibitors. To provide insights into the inhibitory and binding mechanisms of xanthone-based inhibitors toward alpha-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 alpha-helix content of the secondary structure of alpha-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 pi-pi stacking interactions with alpha-glucosidase. The fact that 1,3,7-tridroxyxanthone and 1,3-dihydroxybenzoxanthone exhibited significant synergetic inhibition to alpha-glucosidase strongly suggests that both xanthone derivatives simultaneously bind to the distinct noncompetitive sites of yeast's alpha-glucosidase. On the basis of the plausible binding clues, synergetic inhibition can be developed to be a promising strategy to achieve enhanced inhibitory activities.
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