Inhibition of α-glucosidase by melatonin derivatives: insights from kinetics, docking, and molecular dynamics simulations

Abstract

Type 2 diabetes mellitus (T2DM) represents a major global health challenge, emphasizing the need for effective strategies to manage postprandial hyperglycemia. Inhibition of α-glucosidase, a key enzyme involved in carbohydrate digestion, is a well-established therapeutic approach. In this study, melatonin, an indoleamine with diverse biological activities, was investigated as a scaffold for the development of novel α-glucosidase inhibitors. Among the derivatives evaluated, 4EBM emerged as the most potent inhibitor, exhibiting an IC<inf>50</inf> value of 37.20 ± 0.64 μM and demonstrating greater potency than the standard drug, acarbose. Kinetic studies, molecular docking, and molecular dynamics (MD) simulations indicated that 4EBM acts as a competitive inhibitor by directly interacting with key residues (Y158, F178, Q279, R315, and R442) within the α-glucosidase active site. Furthermore, in silico predictions suggested that several derivatives containing naphthalene, biphenyl, or trifluoromethylphenyl moieties exhibited stronger binding affinities than 4EBM. These findings underscore the potential of melatonin derivatives as promising lead compounds for the development of more effective α-glucosidase inhibitors for T2DM management, while also enhancing the current understanding of indoleamine scaffolds in enzyme inhibition.