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  • Perspective
  • Published:

Sustainable production of chemicals by algorithm-assisted (bio)synthesis

Nature Reviews Bioengineering volume 3, pages 791–803 (2025)Cite this article

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Abstract

Although research on computer-assisted planning of organic chemical syntheses dates back to the 1960s, it has only been in recent years that algorithms became powerful enough to autonomously design complete pathways, both in retrosynthetic and forward directions. Some of these modern programmes can plan chemically correct routes to complex targets and multiple such designs have now been validated by experiment. With chemical correctness secured, the next frontier for machines is to help design syntheses that are green (for example, in terms of conditions applied), sustainable (in terms of resources used) or circular (for example, in terms of waste feedstocks being revalorized). This Perspective argues that several parts of this challenge can benefit from close collaboration between synthetic chemists and bioengineers — for instance, to design better metrics of the environmental impact of syntheses or to develop algorithms with which to delineate the substrate scope of enzymatic transformations. Computers able to plan efficient and greener routes combining chemical and enzymatic steps will have a powerful and lasting impact on the production of fine chemicals.

Key points

  • Advances in reaction network theory and artificial intelligence have already enabled the development of several fully automated synthetic planners.

  • In terms of strictly chemical aspects, the best algorithms are currently on par with human experts. Moreover, they surpass humans in their ability to score syntheses against multiple criteria at once.

  • Multiparametric evaluation is important to prioritize syntheses that meet the demands of greenness and sustainability.

  • Bringing more enzymes into organic synthesis is a largely unmet need of the fine-chemical industry and yet another opportunity where chemistry, bioengineering and artificial intelligence can productively collaborate on algorithms to approximate the substrate scope of enzymes.

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Fig. 1: Backward and forward computer-assisted synthesis.
Fig. 2: A small fragment of a network of algorithmically designed syntheses of drugs sourced from waste substrates.
Fig. 3: Degradations of quinine into smaller but value-added chemicals.

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Acknowledgements

B.A.G., N.O. and E.L. were supported by the Institute for Basic Science, Korea (project code IBS-R020-D1). A.Ż.-D. acknowledges support from the National Center of Science, NCN, Poland (award SONATA 2020/39/D/ST4/01890).

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Authors and Affiliations

  1. Center for Algorithmic and Robotized Synthesis (CARS), Institute for Basic Science (IBS), Ulsan, Republic of Korea

    Bartosz A. Grzybowski, Natalia Onishchenko & Eric S. Larsen

  2. Department of Chemistry, Ulsan Institute of Science and Technology, UNIST, Ulsan, Republic of Korea

    Bartosz A. Grzybowski

  3. Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

    Bartosz A. Grzybowski & Anna Żądło-Dobrowolska

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B.A.G. wrote the manuscript with the help of other co-authors.

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Biosecure act: https://www.pharmaceutical-technology.com/analyst-comment/biosecure-act-wuxi-drugs-us-market/

Living Foundries: https://www.darpa.mil/news-events/2021-12-08

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Grzybowski, B.A., Żądło-Dobrowolska, A., Onishchenko, N. et al. Sustainable production of chemicals by algorithm-assisted (bio)synthesis. Nat Rev Bioeng 3, 791–803 (2025). https://doi.org/10.1038/s44222-025-00312-7

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