AI-Driven Discovery Uncovers Potential Treatment for Acute Glaucoma

Acute glaucoma, characterized by retinal ganglion cell (RGC) death due to acute ocular hypertension, is a sight-threatening condition. A team of researchers from Chinese institutions, led by Dr. Yuanxu Gao and Professor Zhang Kang, have identified Receptor-interacting protein kinase 3 (RIPK3), a mediator of necroptosis, as a promising therapeutic target for protecting RGCs. Leveraging artificial intelligence (AI), a recent study has identified HG9-91-01 as a potential neuroprotective compound for the treatment of acute glaucoma.

The Role of RIPK3 in Acute Glaucoma

RIPK3 plays a central role in necroptosis, a form of programmed cell death contributing to RGC damage in acute glaucoma. While RIPK3 is a viable target for therapy, the mechanisms and agents to effectively inhibit it remain underexplored. The use of AI technologies in drug discovery offers a powerful approach to accelerate the identification of therapeutic candidates.

Study Methodology

To identify RIPK3 inhibitors, researchers used an acute ocular hypertension model to replicate pathological ocular hypertension in vivo. AI techniques, including large language models and graph neural networks, were employed to screen for target compounds. The selected candidates underwent rigorous validation using:

       • Molecular simulations: Molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction, and molecular dynamics simulations.

       • Biological experiments: Western blotting and fluorescence staining in vitro and in vivo.

Key Findings

AI-Driven Drug Discovery

AI identified five promising RIPK3 inhibitor candidates, with HG9-91-01 showing the most significant neuroprotective effects:

       • Enhanced RGC Survival: HG9-91-01 preserved RGC morphology and integrity under hypoxia and glucose deficiency.

       • Retinal Structure Protection: In an acute glaucoma model, HG9-91-01 reduced retinal layer loss and safeguarded the retinal structure.

Mechanism of Action

The neuroprotective effects of HG9-91-01 were closely linked to the inhibition of PANoptosis—a process combining apoptosis, pyroptosis, and necroptosis.

       • HG9-91-01 regulated key proteins involved in these cell death pathways, suppressing their expression and preventing RGC death.

Conclusion

This study highlights the transformative potential of AI-enabled drug discovery in identifying novel therapies for complex diseases. HG9-91-01, a compound discovered through AI, demonstrates strong neuroprotective properties and could serve as a promising treatment for acute glaucoma. Further research is needed to validate these findings and advance HG9-91-01 toward clinical application.

This breakthrough underscores the value of integrating AI technologies into ophthalmic research, offering new hope for tackling sight-threatening conditions like acute glaucoma.

Reference:

Xing Tu et al, Artificial intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma mouse model, Chinese Medical Journal (2024). DOI: 10.1097/CM9.0000000000003387