Pakistan journal of pharmaceutical sciences · 2026
Network pharmacology and molecular simulation suggest potential mechanisms of sorafenib-induced HFSR.
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Qian Wang Li, Qi Zhang Si, Guo Ling, Qi Li Ji, Hong Liu Li, Zhi Zhao Gui
Аннотация
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.
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.