Chemical language models enable navigation in sparsely populated chemical space

Michael A. Skinnider, R. Greg Stacey, David S. Wishart, Leonard J. Foster

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Deep generative models are powerful tools for the exploration of chemical space, enabling the on-demand generation of molecules with desired physical, chemical or biological properties. However, these models are typically thought to require training datasets comprising hundreds of thousands, or even millions, of molecules. This perception limits the application of deep generative models in regions of chemical space populated by a relatively small number of examples. Here, we systematically evaluate and optimize generative models of molecules based on recurrent neural networks in low-data settings. We find that robust models can be learned from far fewer examples than has been widely assumed. We identify strategies that further reduce the number of molecules required to learn a model of equivalent quality, notably including data augmentation by non-canonical SMILES enumeration, and demonstrate the application of these principles by learning models of bacterial, plant and fungal metabolomes. The structure of our experiments also allows us to benchmark the metrics used to evaluate generative models themselves. We find that many of the most widely used metrics in the field fail to capture model quality, but we identify a subset of well-behaved metrics that provide a sound basis for model development. Collectively, our work provides a foundation for directly learning generative models in sparsely populated regions of chemical space.

Original languageEnglish (US)
Pages (from-to)759-770
Number of pages12
JournalNature Machine Intelligence
Volume3
Issue number9
DOIs
StatePublished - Sep 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Software
  • Human-Computer Interaction
  • Computer Vision and Pattern Recognition
  • Computer Networks and Communications
  • Artificial Intelligence

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