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

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.