Integrated pan-cancer systems biology and structure-based simulation identifies Annona muricata-derived natural...

Indoleamine 2,3-dioxygenase 1 (IDO1) is a central immunometabolic checkpoint that promotes tumor immune evasion through dysregulated tryptophan metabolism, yet first-generation inhibitors have shown limited clinical efficacy. This study developed an integrated in silico framework combining pan-cancer systems biology, GC-MS phytochemical profiling, QSAR modeling, molecular docking, ADMET prediction, density functional theory, 100 ns molecular dynamics simulation, and MM-PBSA analysis to identify Annona muricata-derived putative IDO1 modulators. Analysis of > 20,000 TCGA samples across 33 cancer types revealed significant IDO1 overexpression in 11 tumors (p < 0.001), accompanied by recurrent promoter hypomethylation and context-dependent prognostic associations (hazard ratio up to 2.223 and as low as 0.391), within an immune-activated yet immunoregulatory tumor microenvironment. GC-MS profiling identified 52 phytochemicals, of which 49 compounds were prioritized using a validated QSAR model (R² = 0.991, Q² = 0.931). Structure-based docking highlighted lead compounds with stronger predicted binding affinities than epacadostat, including Compound 1 (-12.3 kcal/mol) and Compound 3 (-9.5 kcal/mol). Molecular dynamics simulations (100 ns) demonstrated ligand-induced stabilization of IDO1, with Compound 1 reducing global conformational deviation (RMSD = 1.568 +/- 0.085 Angstrom) and Compound 3 enhancing active-site stability. MM-PBSA analysis further identified Compound 3 as the most energetically favorable binder (72.11 +/- 35.43 kcal mol⁻¹). Collectively, these computational findings identify Annona muricata-derived phytochemicals as promising putative IDO1-binding scaffolds, suggest testable hypotheses involving hydrophobic pocket engagement and ligand-induced conformational stabilization, and provide a focused rationale for future validation through biochemical IDO1 activity assays, kynurenine quantification, cellular target-engagement studies, and pharmacological evaluation.