By: Li qian Wang, Si qi Zhang, Ling Guo, Ji qi Li, Li hong Liu, Gui zhi Zhao
Keywords: EGFR; HFSR; Molecular dynamics simulation; MAPK1 (ERK2); Network pharmacology; Sorafenib
DOI : 10.36721/PJPS.2026.39.10.272.1
Abstract: Background: Hand–foot skin reaction (HFSR) is a dose-limiting adverse effect of sorafenib, yet its molecular etiology remains elusive. Objectives: This study investigated the potential targets and pathways of sorafenib-induced HFSR using integrated computational methods. Methods: Network pharmacology was used to identify overlapping targets between sorafenib and HFSR. After pathway enrichment, hub targets were analyzed via molecular docking and 100-ns molecular dynamics (MD) simulations to assess binding stability. Results: Network analysis identified 71 targets, primarily in the MAPK/ERK and PI3K-Akt pathways. EGFR and MAPK1 (ERK2) were identified as key hubs. MD simulations revealed that sorafenib maintains superior structural stability when complexed with EGFR rather than with ERK2. Conclusion: Computational evidence suggests that off-target engagement and RTK-MAPK/PI3K dysregulation mediate HFSR. These findings provide a mechanistic basis for mitigating sorafenib-induced toxicity, pending experimental validation.
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