Citation: Huijuan Luo, Haiyue Zuo, Jianzhong Zhu, Juanjuan Zhao, Roufen Chen, Xinle Yang, Fangqi Cao, Ruohan Lou, Xiaowu Dong, Yangyang Bian, Ligen Lin. Computer-aided discovery of peptidyl arginine deiminase 4 inhibitors to suppress NETosis and accelerate diabetic wound healing[J]. Chinese Chemical Letters, ;2026, 37(6): 111510. doi: 10.1016/j.cclet.2025.111510 shu

Computer-aided discovery of peptidyl arginine deiminase 4 inhibitors to suppress NETosis and accelerate diabetic wound healing

Huijuan Luo ^{a, 1} ,
Haiyue Zuo ^{b, 1} ,
Jianzhong Zhu ^{a, c, 1} ,
Juanjuan Zhao ^b ,
Roufen Chen ^d ,
Xinle Yang ^d ,
Fangqi Cao ^a ,
Ruohan Lou ^a ,
Xiaowu Dong ^d ,
Yangyang Bian ^{b, *,} ,
Ligen Lin ^{a, e, *,}

a.
State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
b.
Key Laboratory of Resource Biology and Modern Biotechnology in Western China, College of Life Science, Northwest University, Xi'an 710069, China
c.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark
d.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
e.
Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau 999078, China

bianyy@nwu.edu.cn

ligenl@um.edu.mo

Received Date: 7 May 2025
Revised Date: 20 June 2025
Accepted Date: 25 June 2025
Available Online: 25 June 2025

Figures(4)

Neutrophil extracellular traps (NETs) are a significant unfavorable factor for wound healing in diabetes. Citrullination of histone by peptidyl arginine deiminase 4 (PAD4) is the prerequisite for NETs formation. Therefore, PAD4 inhibitors are a promising NETs-targeting strategy to accelerate diabetic wound healing. Herein, a virtual screening workflow incorporating molecular docking and molecular dynamics was performed on a library of U.S. Food and Drug Administration (FDA)-approved drugs, resulting in the identification of gliquidone as a new PAD4 inhibitor. Gliquidone binds directly to PAD4, inhibits its activity, and interrupts NETs formation in neutrophils, which in turn rescues functional impairment in fibroblasts. Furthermore, in streptozotocin-induced diabetic mice, gliquidone accelerates wound healing. Taken together, gliquidone was successfully identified as a new PAD4 inhibitor through a computer-aided virtual screening pipeline, which might be a therapeutic agent against diabetic foot ulcers.
- Peptidyl arginine deiminase 4,
- Molecular docking and molecular dynamics,
- Neutrophil extracellular traps,
- Gliquidone,
- Diabetic wound healing
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沈阳化工大学材料科学与工程学院沈阳 110142