Crowdsourced mapping of unexplored target space of kinase inhibitors

Nat Commun. 2021 Jun 3;12(1):3307. doi: 10.1038/s41467-021-23165-1.

Abstract

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Benchmarking
  • Crowdsourcing
  • Databases, Pharmaceutical
  • Deep Learning
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Humans
  • Kinetics
  • Machine Learning
  • Models, Biological
  • Models, Chemical
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Proteomics
  • Regression Analysis

Substances

  • Protein Kinase Inhibitors
  • Protein Kinases