Computational Exploration of Phenolic Compounds from Endophytic Fungi as α-Glucosidase Inhibitors for Diabetes Management.

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Diabetes has become a global epidemic, affecting even the younger people on an alarming scale. Inhibiting intestinal α-glucosidase is one of the key approaches to managing type 2 diabetes (T2D). In the present study, phenolic compounds (PCs) produced by endophytic fungi as potential α-glucosidase inhibitors (AGIs) are explored through ADMET profiling, molecular docking, and molecular dynamics (MD) Simulations. After 150 PCs were screened for their drug-likeness and toxicity properties, 45 molecules were selected. These were subjected to molecular docking studies against human N-terminal maltase-glucoamylase (NtMGAM). Based on binding energy and IC50 values, the best five PCs from different chemical classes (depsidones, phenolic acids, butenolides, furanones, and polyketides) were studied for their binding dynamics with NtMGAM employing all-atom MD simulations. Among the five ligands analyzed, the methybutyrolactone III (BUT)-NtMGAM complex exhibited significantly higher active site flexibility, indicating a conformational change in response to ligand binding. BUT interacted specifically with both key residues, Asp443 and Phe575, critical for enzyme-inhibitor stability. These interactions, coupled with increased flexibility, suggest enhanced stabilization of BUT in the active site pocket. BUT also exhibited one of the most favorable toxicity profiles among molecules analyzed using ProTox 3.0. Molecular mechanics Poisson-Boltzmann surface area calculations confirmed that BUT had the highest binding energy (-35.01 kcal/mol) driven by substantial van der Waals and electrostatic interactions. Another butenolide derivative, aspernolide (ALD) ranked second in the binding energy score (-31.13 kcal/mol). These findings suggest that PCs possessing butenolide scaffolds, like BUT and ALD, hold great promise as potential AGIs for managing T2D. These findings, however, need to be further validated through in vivo experimentation.