Deoxynojirimycin derivatives as potent α-glucosidase inhibitors: in silico ADMET evaluation, molecular dynamics and in vitro validation studies.

Abstract

α-Glucosidase plays a critical role in digesting carbohydrates, leading to an increase in postprandial glucose levels, which contributes to the development and progression of diabetes. By inhibiting this enzyme, it is possible to manage postprandial hyperglycemia, thereby reducing the risk of developing or exacerbating diabetes. The primary aim of our study was to identify and evaluate potential α-glucosidase inhibitors from a series of deoxynojirimycin derivatives, using a combination of binding affinity analysis, simulation studies, and in vitro experiments. 371 deoxynojirimycin analogs were screened based on their compliance with Lipinski's Rule of Five and favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters. Among these, compound MG257 (C₁₀H₂₁NO₄) stood out due to its strong binding interactions with the active site residues of α-glucosidase, as demonstrated through virtual screening and docking studies. In our in vitro analysis, MG257 (C₁₀H₂₁NO₄) demonstrated a notably potent α-glucosidase inhibitory activity with an IC₅₀ value of 0.44 ± 0.18 µM, surpassing the standard inhibitor miglitol, which exhibited an IC₅₀ of 0.64 ± 0.26 µM. Furthermore, molecular dynamics simulations conducted over 100 ns revealed that MG257 maintained excellent stability, further supporting its potential as a reliable inhibitor. Enzyme kinetics studies also confirmed that MG257 inhibits α-glucosidase competitively, reinforcing the findings from the molecular docking and simulation data. These comprehensive results, combining in silico and in vitro approaches, underscore the drug-likeness of MG257 and its promising pharmacokinetic profile. In conclusion, our findings suggest that MG257 (C₁₀H₂₁NO₄) is a potent α-glucosidase inhibitor with significant potential as a novel therapeutic agent for the management of Type 2 diabetes, warranting further research and development.