Deep learning enables rapid identification of potent DDR1 kinase inhibitors.

Journal: Nature biotechnology
PMID: 31477924

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.

Authors

  • Alex Zhavoronkov
    Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, Baltimore, Maryland, USA.
  • Yan A Ivanenkov
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Alex Aliper
    Pharma.AI Department , Insilico Medicine, Inc. , Baltimore , Maryland 21218 , United States.
  • Mark S Veselov
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Vladimir A Aladinskiy
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Anastasiya V Aladinskaya
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Victor A Terentiev
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Daniil A Polykovskiy
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Maksim D Kuznetsov
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Arip Asadulaev
    Computer Technologies Lab , ITMO University , St. Petersburg 197101 , Russia.
  • Yury Volkov
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Artem Zholus
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Rim R Shayakhmetov
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Alexander Zhebrak
    Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, Baltimore, Maryland, USA.
  • Lidiya I Minaeva
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Bogdan A Zagribelnyy
    Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.
  • Lennart H Lee
    WuXi AppTec Co., Ltd, Shanghai, China.
  • Richard Soll
    WuXi AppTec Co., Ltd, Shanghai, China.
  • David Madge
    WuXi AppTec Co., Ltd, Shanghai, China.
  • Li Xing
    WuXi AppTec Co., Ltd, Shanghai, China.
  • Tao Guo
    Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Hangzhou, Zhejiang, China.
  • Alán Aspuru-Guzik
    Departments of Chemistry, Computer Science, University of Toronto St. George Campus Toronto ON Canada.

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