Computational Screening of Alternaria Metabolites as Potential DPP-4 Inhibitors: ADMET, Molecular Docking, Molecular Dynamics, and Network Pharmacology Analysis

Type 2 diabetes represents a major global health burden, necessitating the development of safer and more effective therapeutic strategies. While fungi exhibit exceptional metabolic diversity, the genus Alternaria remains largely unexplored for antidiabetic bioactive compounds. This study investigates Alternaria as a potential source of natural inhibitors against dipeptidyl peptidase-4 (DPP4), a validated therapeutic target regulating blood glucose levels through incretin hormone modulation. A library of 278 Alternaria metabolites was systematically screened using an integrated computational workflow. Candidates were prioritized through ADMET profiling to ensure drug-likeness and molecular docking to identify high-affinity binders. Subsequently, molecular dynamics simulations and MM-PBSA calculations substantiated the stability and binding free energy of the top hits. Additionally, network pharmacology approaches were employed to predict mechanistic pathways, elucidating the lead compound's potential as a multi-target therapeutic. Among the prioritized candidates, Anthrininone B (–23.35 ± 3.40 kcal/mol) and Alternatain D (–20.06 ± 4.07 kcal/mol) exhibited significantly stronger binding affinities than the reference drug linagliptin (–10.55 ± 0.34 kcal/mol). Structural analysis revealed that Anthrininone B achieved superior inhibition through stable interactions with Ser630, Tyr547, and the S2′ pocket residue Trp629, emerging as the most promising natural DPP4 inhibitor. Further analysis characterized Anthrininone B as a pleiotropic candidate modulating critical diabetic pathways, including cAMP-mediated insulin secretion, inflammatory suppression via NF-κB1, and β-cell preservation through HIF1α. These findings highlight Alternaria metabolites as promising candidates for natural-based antidiabetic therapeutics and support the further experimental validation of Anthrininone B.