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Published on: July 14, 2016
Artificial intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma
Xing Tu1,2,3,4, Zixing Zou2, Jiahui Li2,3,5
1Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, 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 assistance.
Methods:
An acute ocular hypertension model was used to simulate pathological ocular hypertension in 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 and in vivo .
Results:
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 effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis.
Conclusion:
AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
Insights
Artificial intelligence identified HG9-91-01, a novel RIPK3 inhibitor, demonstrating neuroprotective effects against acute glaucoma by inhibiting PANoptosis. This compound shows promise for treating retinal ganglion cell death in glaucoma patients.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Acute glaucoma causes retinal ganglion cell (RGC) death via ocular hypertension.
- Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis and is a potential therapeutic target for RGC death.
- Limited understanding exists regarding RIPK3-targeting agents for glaucoma treatment.
Purpose of the Study:
- To discover novel RIPK3 inhibitors for acute glaucoma treatment using artificial intelligence (AI).
- To validate AI-identified drug candidates through molecular simulations and biological experiments.
Main Methods:
- AI, including large language and graph neural network models, was used to identify RIPK3 inhibitors.
- In silico validation involved molecular docking, ADMET prediction, and molecular dynamics simulations.
- In vitro and in vivo validation included Western blotting and fluorescence staining in an acute ocular hypertension model.
Main Results:
- AI identified HG9-91-01, which demonstrated neuroprotective effects in an acute glaucoma model.
- HG9-91-01 protected RGC cells from hypoxia/glucose deficiency and preserved retinal structure.
- Neuroprotection was linked to the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis) by regulating key proteins.
Conclusions:
- AI-enabled drug discovery successfully identified HG9-91-01 as a potential therapeutic agent for acute glaucoma.
- HG9-91-01 warrants further investigation for its efficacy in treating glaucoma-related RGC death.
