The DOI matches its Crossref record; 49 of the 57 references it cites were found in a registry or an index.
Deep learning enables rapid identification of potent DDR1 kinase inhibitors
Abstract
We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice.
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“With the help of GEN-TRL (https:// github. com / insil icome dicine/ GENTRL), Zhavoronkov et al. discovered novel inhibitors of an enzyme, DDR1 kinase [118].”
BackgroundMethod
Metadata
- Authors
- Zhavoronkov, A., Ivanenkov, Y. A., Aliper, A., Veselov, M. S., Aladinskiy, V. A., Aladinskaya, A. V., Terentiev, V. A., Polykovskiy, D. A., Kuznetsov, M. D., Asadulaev, A., Volkov, Y., Zholus, A., Shayakhmetov, R. R., Zhebrak, A., Minaeva, L. I., Zagribelnyy, B. A., Lee, L. H., Soll, R., Madge, D., Xing, L., Guo, T., & Aspuru-Guzik, A.
- Affiliations
- WuXi AppTec (China) (CN)
- Corresponding author
- Zhavoronkov, Alex
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2019-09
- Volume
- 37
- Issue
- 9
- Pages
- 1038-1040
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2971690404
- Cited by
- 1,573
- References
- 57
- Citations by year
- 2026: 320 · 2025: 306 · 2024: 224 · 2023: 178 · 2022: 169 · 2021: 206 · 2020: 144 · 2019: 22
- FWCI
- 92.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nvidia
- Nature
- School of Medicine, University of New Mexico
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Materials Science › Materials Chemistry › Machine Learning in Materials Science
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- DDR1, deep generative models, drug discovery, fibrosis, pharmacokinetics
- MeSH terms
- Discoidin Domain Receptor 1, Deep Learning, Animals, Dogs, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Microsomes, Liver, Models, Molecular, Protein Conformation, Molecular Structure, Mice, Rats
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