Biological evaluation of 9-(1H-Indol-3-yl) xanthen-4-(9H)-ones derivatives as noncompetitive α-glucosidase inhibitors: kinetics and molecular mechanisms
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The α-Glucosidase plays a key role in attenuation of postprandial hyperglycemia in diabetic patients. In this study, a class of 9-(1H-Indol-3-yl) xanthen-4-(9H)-ones derivatives (M1-M20) were evaluated for their α-Glucosidase inhibitory activity. The inhibitory activities of these compounds were evaluated via inhibition kinetics, molecular dynamic (MD) simulations, ensemble docking, and linear quantitative structure–activity relationship (QSAR) models. The results from the serial kinetic studies demonstrated that most of the ligands could directly inactivate enzyme activity in a dose-dependent manner. A typical non-competitive type of inhibition was observed, with compound M15 showing the highest inhibitory activity among the ligands tested. Also, MD simulations and ensemble docking studies on α-glucosidase homology model confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of synthetic ligands were also disclosed. The QSAR studies showed that the electronegative and oxygen-containing functional groups of indolyl-xanthone structures play a significant role in low-to-moderate inhibitory properties of these potentially anti-diabetic drugs against α-Glucosidase enzyme. Thus, our studies provide important molecular mechanisms delineating α-Glucosidase inhibition, which could aid in development of new drugs for type 2 diabetes mellitus treatment.
Keywordsα-Glucosidase Inhibition kinetics Non-competitive inhibition Molecular dynamics simulation Ensemble docking OSAR
This research was supported by the University of Tehran, Iran National Science Foundation (INSF), Iran National Elites Foundation (INEF), UNESCO Chair on Interdisciplinary Research in Diabetes at University of Tehran, Iran Society of Biophysical Society and Research Councils of Shiraz University are gratefully acknowledged.
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Conflict of interest
The authors declare that they have no conflict of interest.
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