Deep Learning Enhancing Kinome-Wide Polypharmacology Profiling: Model Construction and Experiment Validation.

Journal: Journal of medicinal chemistry
Published Date: Aug 15, 2019

Abstract

The kinome-wide virtual profiling of small molecules with high-dimensional structure-activity data is a challenging task in drug discovery. Here, we present a virtual profiling model against a panel of 391 kinases based on large-scale bioactivity data and the multitask deep neural network algorithm. The obtained model yields excellent internal prediction capability with an auROC of 0.90 and consistently outperforms conventional single-task models on external tests, especially for kinases with insufficient activity data. Moreover, more rigorous experimental validations including 1410 kinase-compound pairs showed a high-quality average auROC of 0.75 and confirmed many novel predicted "off-target" activities. Given the verified generalizability, the model was further applied to various scenarios for depicting the kinome-wide selectivity and the association with certain diseases. Overall, the computational model enables us to create a comprehensive kinome interaction network for designing novel chemical modulators or drug repositioning and is of practical value for exploring previously less studied kinases.

Authors

  • Xutong Li
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Zhaojun Li
    School of Information Management, Dezhou University, Shandong, 253023, China.
  • Xiaolong Wu
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhaoping Xiong
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Tianbiao Yang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Zunyun Fu
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Xiaohong Liu
    Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China. Electronic address: lvj221@163.com.
  • Xiaoqin Tan
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Feisheng Zhong
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xiaozhe Wan
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Dingyan Wang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Xiaoyu Ding
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Ruirui Yang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Hui Hou
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Chunpu Li
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Hong Liu
    Key Laboratory of Grain and Oil Processing and Food Safety of Sichuan Province, College of Food and Bioengineering, Xihua University Chengdu 610039 China xingyage1@163.com.
  • Kaixian Chen
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Hualiang Jiang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • Mingyue Zheng
    School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang Province, China.

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