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Artificial intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma mouse model

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中华医学杂志(英文版) 2025年第2期138卷 2024 Dec 23页

作者： Tu Xing Zou Zixing Li Jiahui Zeng Simiao Luo Zhengchao Li Gen Gao Yuanxu Zhang Kang Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou Guangdong China Guangzhou National Laboratory Guangzhou International Bio Island Guangzhou Guangdong China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science Guangzhou Guangdong China University of Chinese Academy of Sciences Beijing China Guangzhou Women and Children’s Medical Center Guangzhou Medical University Guangzhou Guangdong China Department of Big Data and Biomedical AI College of Future Technology Peking University Beijing China Institute for Artificial Intelligence in Medicine and Faculty of Medicine Macau University of Science and Technology Macao Special Administrative Region China

Background: Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI ***: An acute ocular hypertension model was used to simulate pathological ocular hypertensionin vivo. We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining)in vitro andin ***: AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective e

关键词： Virtual screening AI model PANoptosis acute ocular hypertension HG9-91-01 glucoma

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