Phenyllactic Acid from Saccharomyces boulardii Modulates EGFR & CXCR4: A Network Pharmacology & Molecular Dynamics Study

Abstract

Saccharomyces boulardii is a probiotic yeast widely used for managing gastrointestinal disorders such as irritable bowel disease and antibiotic-associated diarrhea. Bioactive compounds derived from S. boulardii exhibit anti-inflammatory, antimicrobial, and intestinal barrier-protective properties. However, the role of bioactive compounds in management of cancer remains unexplored. Using network pharmacology and molecular modeling, 116 bioactive compounds retrieved from literature, were analyzed. Gene targets of shortlisted 9 compounds through ADMET criteria were analyzed via protein-protein interaction (PPI) networks, Gene Ontology, KEGG, and Reactome enrichment. Protein-ligand interactions were evaluated through molecular docking. Complex stability was assessed using 50 ns molecular dynamics simulations followed by MM/PBSA binding free energy calculations. A total of 115 overlapping targets associated with gastrointestinal, neurological, and oncological disorders were identified. EGFR, STAT3, CTNNB1, and NFKB1 emerged as key hub proteins, with enrichment in PI3K-Akt, JAK-STAT, and PD-1/PD-L1 pathways. Phenyllactic acid was identified as the central metabolite through compound-target network analysis. Molecular docking and dynamics simulations confirmed stable binding of phenyllactic acid with EGFR and CXCR4, supported by consistent RMSD values (0.2-0.35 nm) and localized RMSF fluctuations. Key binding residues included Cys775, Thr790, Asp855, and Met766 for EGFR, and Trp94, Asp97, Tyr116, and Val112 for CXCR4. MM/PBSA calculations confirmed favourable binding energies of -26.2 kcal/mol and -24.6 kcal/mol for EGFR and CXCR4 respectively. Phenyllactic acid from S. boulardii acts as a multi-target modulator of EGFR and CXCR4, simultaneously influencing proliferative and migratory oncogenic signaling, warranting further experimental validation in cancer management.