Unveiling the molecular mechanisms of clozapine-induced seizures: a network pharmacology and molecular docking-based investigation
- 1Laboratory of Computational Biology and Animal Imaging Center (CBAC-Lab), Tianjin Anding Hospital; Department of Psychiatry and Psychology, College of Basic Medical Sciences, Tianjin Medical University, Mental Health Center of Tianjin Medical University
- 2The Third People’s Hospital of Hulunbuir (Hulunbeier Mental Health Centre)
- 3Peking University Cancer Hospital (Inner Mongolia Campus)
Abstract
Clozapine is the preferred treatment for refractory schizophrenia. However, clozapine use is constrained by the risk of clozapine‑induced seizures (CISs). The molecular mechanisms behind CISs are complex and poorly understood. The objective of this study was to identify the core targets and signaling pathways contributing to CISs using network pharmacology and molecular docking. Potential targets for clozapine and seizures were screened using multiple databases, and overlapping targets were identified. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualized in Cytoscape to identify core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the core targets were performed, and a disease-target-pathway-drug network was constructed. The docking of clozapine with the core targets was evaluated to determine the stability of their interactions. Of the 656 potential targets for clozapine and 1260 targets for seizure, 104 targets overlapped. PPI analysis of the overlapping targets yielded 12 core targets. KEGG pathway enrichment analysis demonstrated that glutamatergic, dopaminergic, and GABAergic synapses may be key pathways mediating CIS. The molecular docking results showed that clozapine had strong binding affinities for the core targets, BDNF, GRIN2B, GRIN2A, and GAD1. Thus, clozapine may interfere with the glutamatergic, dopaminergic, and GABAergic synaptic pathways by modulating BDNF, GRIN2B, GRIN2A, and GAD1. Modulation of these core targets may contribute to excitatory–inhibitory imbalance in the central nervous system, thereby potentially increasing seizure susceptibility. This study provides an integrative perspective on the potential pathophysiology of CIS and suggests directions for future experimental validation and risk intervention strategies.
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BibTeX
@article{lian2026unveiling,
title = {{Unveiling the molecular mechanisms of clozapine-induced seizures: a network pharmacology and molecular docking-based investigation}},
author = {Daxiang Lian and Jian Li and Bo Han and Xia Liu and Ranli Li and Xiaoyan Ma and Fuqiang Mao and Chuanjun Zhuo},
journal = {Schizophrenia},
year = {2026},
month = jun,
doi = {10.1038/s41537-026-00773-8},
url = {https://doi.org/10.1038/s41537-026-00773-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - Unveiling the molecular mechanisms of clozapine-induced seizures: a network pharmacology and molecular docking-based investigation
AU - Daxiang Lian
AU - Jian Li
AU - Bo Han
AU - Xia Liu
AU - Ranli Li
AU - Xiaoyan Ma
AU - Fuqiang Mao
AU - Chuanjun Zhuo
PY - 2026
DA - 2026/06/01
JO - Schizophrenia
DO - 10.1038/s41537-026-00773-8
UR - https://doi.org/10.1038/s41537-026-00773-8
AB - Clozapine is the preferred treatment for refractory schizophrenia. However, clozapine use is constrained by the risk of clozapine‑induced seizures (CISs). The molecular mechanisms behind CISs are complex and poorly understood. The objective of this study was to identify the core targets and signaling pathways contributing to CISs using network pharmacology and molecular docking. Potential targets for clozapine and seizures were screened using multiple databases, and overlapping targets were identified. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualized in Cytoscape to identify core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the core targets were performed, and a disease-target-pathway-drug network was constructed. The docking of clozapine with the core targets was evaluated to determine the stability of their interactions. Of the 656 potential targets for clozapine and 1260 targets for seizure, 104 targets overlapped. PPI analysis of the overlapping targets yielded 12 core targets. KEGG pathway enrichment analysis demonstrated that glutamatergic, dopaminergic, and GABAergic synapses may be key pathways mediating CIS. The molecular docking results showed that clozapine had strong binding affinities for the core targets, BDNF, GRIN2B, GRIN2A, and GAD1. Thus, clozapine may interfere with the glutamatergic, dopaminergic, and GABAergic synaptic pathways by modulating BDNF, GRIN2B, GRIN2A, and GAD1. Modulation of these core targets may contribute to excitatory–inhibitory imbalance in the central nervous system, thereby potentially increasing seizure susceptibility. This study provides an integrative perspective on the potential pathophysiology of CIS and suggests directions for future experimental validation and risk intervention strategies.
SN - 2754-6993
ER -