Synthesis, Biological Evaluation, and Computational Studies of Phenolic N-Acetylglucosamine Glycosides as α-Glucosidase Inhibitors

TL;DR

This study explores how modifying phenolic compounds with N-acetylglucosamine improves their ability to inhibit α-glucosidase, a target for treating type 2 diabetes.

Contribution

The study introduces NAG glycosides as a novel class of α-glucosidase inhibitors with enhanced activity and binding affinity.

Findings

NAG glycosylation significantly improved α-glucosidase inhibitory activity compared to parent phenolic compounds.

Glycoside 3a showed inhibitory effects comparable to acarbose and metformin at high concentrations.

NAG glycosides increased enzyme conformational flexibility and structural looseness, reducing activity.

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic diseases, and inhibition of α-glucosidase activity represents an effective therapeutic strategy. Chitin is the most abundant renewable polysaccharide in the ocean, with its monosaccharide being N-acetylglucosamine (NAG). To evaluate the potential of NAG glycosides as novel α-glucosidase inhibitors, three common phenolic compounds were modified via NAG glycosylation. Their inhibitory activities were assessed at both the enzymatic and cellular levels. In addition, density functional theory (DFT), molecular dynamics (MD) simulations, and molecular docking analyses were employed to systematically investigate the effects of NAG glycosylation on enzyme inhibition and the underlying mechanisms. Compared with the parent phenolic compounds, NAG glycosides exhibited significantly enhanced α-glucosidase inhibitory activity, with NAG introduction markedly improving their binding affinity to α-glucosidase. Among them, glycoside 3a displayed the optimal inhibitory effect, comparable to acarbose, and at the cellular level, its activity at high concentrations was comparable to or slightly higher than that of metformin. Circular dichroism (CD) and MD analyses indicated that glycoside 3a increased the conformational flexibility of key residues and enhanced the structural looseness of the enzyme, thereby inhibiting its activity. NAG glycosides constitute a promising class of marine-derived α-glucosidase inhibitors, warranting further structural optimization and rational design to enhance their activity and selectivity.

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