Zhang Ying, Li Ranli, Chen Ximing, Li Yachen, Zhang Qiuyu, Yang Lei, Wang Lina, Sun Yun, Mao Fuqiang, Zhuo Chuan Jun
Computational Biology Center, Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, Tianjin, China.
Department of Psychiatry and Psychology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
CNS Neurosci Ther. 2025 Jan;31(1):e70206. doi: 10.1111/cns.70206.
Clozapine exhibits significant therapeutic efficacy in schizophrenia, especially treatment-resistant schizophrenia. However, clozapine can cause agranulocytosis, a fatal adverse effect, and the aim of this study is to explore this mechanism based on network pharmacology and molecular docking.
Six and two databases were used to identify targets associated with clozapine and agranulocytosis, respectively. The bioinformatics online platform was used to identify overlaps between the drug and disease targets. The protein-protein interaction (PPI) network was characterized using Cystoscope 3.10.1 and STRING. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were analyzed using the DAVID online platform. A drug-target-pathway-disease network was constructed utilizing Cystoscope 3.10.1. The Auto Dock Vina and PyMOL software were used to verify the molecular docking of clozapine and core targets.
The analysis revealed 188 overlapping targets. The PPI and KEGG enrichment pathway analyses demonstrated that clozapine induces agranulocytosis by modulating the hematopoietic cell lineage and JAK-STAT signaling pathways via interleukin-3 (IL3), IL6, IL2 receptor subunit alpha (IL2RA), and granulocyte colony-stimulating factor. Binding energies between clozapine and core targets were favorable (< -7.0 kcal/mol).
Clozapine-induced agranulocytosis may be linked to the JAK-STAT inflammatory signaling pathway through inflammatory and hematopoietic-related cytokines. Our findings enhance our comprehension of the potential mechanisms underlying clozapine-induced agranulocytosis.
氯氮平在精神分裂症，尤其是难治性精神分裂症中表现出显著的治疗效果。然而，氯氮平可导致粒细胞缺乏症这一致命不良反应，本研究旨在基于网络药理学和分子对接探索其机制。
分别使用六个和两个数据库来识别与氯氮平和粒细胞缺乏症相关的靶点。利用生物信息学在线平台识别药物和疾病靶点之间的重叠。使用Cystoscope 3.10.1和STRING对蛋白质-蛋白质相互作用（PPI）网络进行表征。使用DAVID在线平台分析京都基因与基因组百科全书（KEGG）和基因本体论（GO）。利用Cystoscope 3.10.1构建药物-靶点-通路-疾病网络。使用Auto Dock Vina和PyMOL软件验证氯氮平和核心靶点的分子对接。
分析显示有188个重叠靶点。PPI和KEGG富集通路分析表明，氯氮平通过白细胞介素-3（IL3）、白细胞介素-6（IL6）、白细胞介素-2受体α亚基（IL2RA）和粒细胞集落刺激因子调节造血细胞谱系和JAK-STAT信号通路，从而诱导粒细胞缺乏症。氯氮平和核心靶点之间的结合能良好（< -7.0 kcal/mol）。
氯氮平诱导的粒细胞缺乏症可能通过炎症和造血相关细胞因子与JAK-STAT炎症信号通路相关。我们的研究结果增强了我们对氯氮平诱导粒细胞缺乏症潜在机制的理解。
