Computational insight into synthetic alpha-glucosidase inhibitors: Homology modeling, docking, and molecular dynamics simulation

Abstract

Diabetes mellitus is a metabolic disorder with high prevalence. As hyperglycemia is the main manifestation of diabetes, controlling postprandial hyperglycemia by inhibiting carbohydrate digestion is important to treat the disease. α-glucosidase is one of the carbohydrate hydrolyzing enzymes that breaks carbohydrates into monosaccharides and thus causes hyperglycemia. Therefore, α-glucosidase is an attractive target to decrease blood glucose level by suppressing carbohydrate digestion. There are clinically available α-glucosidase inhibitor drugs. However, these drugs are associated with adverse effects. Therefore, novel drugs with high efficacy and low adverse effects are needed. Heterocyclic compounds are under investigation to this end. In this study, active heterocyclic inhibitors were selected. The probable mode of action for these compounds was investigated through molecular docking and molecular dynamics (MD) simulation after the human α-glucosidase structure was built via homology modeling. The pharmacokinetic properties of the compounds were also assessed. The docking study showed that some of them have high binding potential to the α-glucosidase. However, the compounds with high binding potential gave enzyme-compound complexes with moderate stability. Compound 5 gave a complex with relatively higher stability. The computational pharmacokinetic study revealed that the compounds except compounds 12 and 13 would have good absorption or permeability for oral administration. Understanding the mechanism of action for the existing active compounds will be helpful to pursue the research for further applications and to design novel compounds with similar scaffolds. The findings of this study need further investigation through in vitro and in vivo methods.

Keywords

• alpha-glucosidase
• docking
• homology modeling
• MD simulation
• pharmacokinetic

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