Biological and Medicinal Chemistry

JAEGER – Hunting for Antimalarials with Generative Chemistry



Recent advances in generative modeling allow designing novel compounds through deep neural networks. One such neural network model, the Junction Tree Variational Auto- Encoder (JT-VAE), excels at proposing chemically valid structures. Based on JT-VAE, we built a generative modeling approach (JAEGER) for finding novel chemical matter with desired bioactivity. Using JAEGER, we designed compounds to inhibit malaria. To prioritize the compounds for synthesis, we used the in-house Profile-QSAR (pQSAR) program, a massively-multitask bioactivity model based on 12,000 Novartis assays. Based on the pQSAR activity predictions, we selected, synthesized, and experimentally profiled two compounds. Both compounds exhibited low nanomolar activity in a malaria proliferation assay as well as a biochemical assay measuring activity against PI(4)K, which is an essential kinase that regulates intracellular development in malaria. The compounds also showed low activity in a cytotoxicity assay. Our findings show that JAEGER is a viable approach for finding novel active compounds for drug discovery.


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Supplementary material

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Supplementary Material
Supplementary Figures and Supplementary Note