Computational Identification and Validation of PDGFRA and HIF1A as Direct Targets of Mycophenolate Mofetil in...

Mycophenolate mofetil (MMF) is widely recognized for its immunosuppressive effects through its active metabolite mycophenolic acid (MPA). This study utilizes computational approaches-molecular docking and molecular dynamics (MD) simulations-to explore MMF' s direct regulatory role in allograft rejection (AR), particularly in liver transplantation.

Potential targets of MMF were retrieved from Super-PRED, while AR-related genes were identified via Gene Set Enrichment Analysis (GSEA). Overlapping genes were analyzed using DAVID for functional enrichment (GO and REACTOME). A PPI network was constructed with STRING and visualized in Cytoscape. Core targets were subjected to molecular docking and MD simulations. Protein expression in liver tissues was validated using the Human Protein Atlas.

GSEA identified 257 AR-associated targets. Intersection with MMF targets revealed 7 core genes. Functional analysis indicated their involvement in key biological processes and pathways. Molecular docking showed strong binding of MMF to core targets, especially HIF1A and PDGFRA, which was further confirmed by stable binding in MD simulations. Human Protein Atlas data indicated specific expression of HIF1A and PDGFRA within mobile immune cells in hepatic vasculature.

This study suggests a novel mechanism by which MMF may directly modulate specific targets, providing a theoretical basis for new MMF-based therapies and supporting further clinical exploration in transplantation immunology.