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Artificial intelligence for natural product drug discovery

Nature Reviews Drug Discovery volume 22, pages 895–916 (2023)Cite this article

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Abstract

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

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Fig. 1: Applications of artificial intelligence in natural product and drug discovery.
Fig. 2: Example compounds discovered using artificial intelligence approaches.
Fig. 3: Predicting biological activities and macromolecular targets from genomic, metabolomic and phenotypic data.
Fig. 4: Chemical featurization techniques.
Fig. 5: Depositing and sharing natural product data: infrastructure and incentives.

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Acknowledgements

All authors thank the Lorentz Center and Leiden University for funding the Lorentz Workshop ‘Artificial Intelligence for Natural Product Drug Discovery’ that laid the foundation for this Review. M.W.M. was supported by funds from the Duchossois Family Institute at the University of Chicago. K.R.D. was supported by the UK Research and Innovation Biotechnology and Biological Sciences Research Council (BB/R022054/1). N.G. was supported by an NSF CAREER award (award number 2047235). J.J.J.v.d.H. was supported by an ASDI eScience grant from the Netherlands eScience Center (award number ASDI.2017.030). N.I.M. is supported by funding from the European Research Council (ERC consolidator grant agreement no. 725523). K.B. was supported by a Novo Nordisk Foundation grant NNF20CC0035580. M.G.G. was supported by ONCODE funding. E.J.N.H. was supported by the LOEWE Center for Translational Biodiversity Genomics and the Funds of the Chemical Industry Germany. M.S. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project-ID 239748522, SFB 1127 ChemBioSys. M.A.B. was supported by the National French Agency (ANR grants 15-CE29-0001 and 20-CE43-0010). C.M.C. was supported by a National Library of Medicine training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). S.F. was supported by MASTS/IbioIC/Xanthella. O.V.K. was funded by the Klaus Faber Foundation. H.K. was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grants NRF 2018R1A5A2023127 and NRF 2022R1F1A107462311). J.M. was supported by a grant from the Research Foundation – Flanders (G061821N). E.R.R. was supported by the US National Science Foundation (DBI-1845890). D.R. was supported, in part, by a Flash Grant from NC Biotech (2021-FLG-3819), a UNC CGIBD Pilot Award (NIH NIDDK DK034987), a Duke Cancer Institute and Duke Microbiome Center Pilot Award (NIH NCI CA014236), the Engineering Research Center for Precision Microbiome Engineering (NSF EEC-2133504), and the Duke Science and Technology Initiative. P.S. acknowledges support from the NCCR Catalysis (grant number 180544), a National Centre of Competence in Research funded by the Swiss National Science Foundation. N.Z. was supported by Germany’s Excellence Strategy – EXC 2124-390838134. H.U.K. was supported by the KAIST Key Research Institute (Interdisciplinary Research Group) Project. R.G.L. was supported by the US NIH (U41-AT008718 and U24-AT010811). S.L.R. was supported by Eawag discretionary funding. M.H.M. was supported by the Leiden University ‘van der Klaauw’ chair for theoretical biology and an ERC Starting Grant (DECIPHER-948770). We thank A. R. Leach for discussion of the content of this manuscript. We thank all participants of the Lorentz Workshop ‘Artificial Intelligence for Natural Product Drug Discovery’ who did not participate in the review writing for providing inspiration through their talks and/or discussions.

Author information

Author notes

  1. These authors contributed equally: Michael W. Mullowney, Katherine R. Duncan, Somayah S. Elsayed, Neha Garg, Justin J. J. van der Hooft, Nathaniel I. Martin, David Meijer, Barbara R. Terlouw.

Authors and Affiliations

  1. Duchossois Family Institute, The University of Chicago, Chicago, IL, USA

    Michael W. Mullowney

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

    Katherine R. Duncan

  3. Department of Molecular Biotechnology, Institute of Biology, Leiden University, Leiden, The Netherlands

    Somayah S. Elsayed, Doris A. van Bergeijk, Chao Du & Gilles P. van Wezel

  4. School of Chemistry and Biochemistry, Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, GA, USA

    Neha Garg

  5. Bioinformatics Group, Wageningen University, Wageningen, The Netherlands

    Justin J. J. van der Hooft, David Meijer, Barbara R. Terlouw, Friederike Biermann & Marnix H. Medema

  6. Department of Biochemistry, University of Johannesburg, Johannesburg, South Africa

    Justin J. J. van der Hooft

  7. Biological Chemistry Group, Institute of Biology, Leiden University, Leiden, The Netherlands

    Nathaniel I. Martin

  8. Institute of Molecular Bio Science, Goethe-University Frankfurt, Frankfurt am Main, Germany

    Friederike Biermann & Eric J. N. Helfrich

  9. LOEWE Center for Translational Biodiversity Genomics (TBG), Frankfurt am Main, Germany

    Friederike Biermann & Eric J. N. Helfrich

  10. The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark

    Kai Blin

  11. Biozentrum, University of Basel, Basel, Switzerland

    Janani Durairaj

  12. Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

    Marina Gorostiola González, Willem Jespers & Gerard J. P. van Westen

  13. ONCODE institute, Leiden, The Netherlands

    Marina Gorostiola González

  14. Center for Digitalization and Digitality, Hochschule Düsseldorf, Düsseldorf, Germany

    Florian Huber

  15. Institut für Mikrobiologie, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland

    Stefan Leopold-Messer

  16. Institute for Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, Jena, Germany

    Kohulan Rajan

  17. School of Chemical Sciences, University of Auckland, Auckland, New Zealand

    Tristan de Rond

  18. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    Jeffrey A. van Santen & Roger G. Linington

  19. Institute for Inorganic and Analytical Chemistry, Friedrich-Schiller University, Jena, Germany

    Maria Sorokina

  20. Pharmaceuticals R&D, Bayer AG, Berlin, Germany

    Maria Sorokina

  21. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA

    Marcy J. Balunas

  22. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA

    Marcy J. Balunas

  23. Équipe “Chimie des Substances Naturelles”, Université Paris-Saclay, CNRS, BioCIS, Orsay, France

    Mehdi A. Beniddir

  24. Structural and Computational Biology Unit, EMBL, Heidelberg, Germany

    Laura M. Carroll

  25. Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA

    Chase M. Clark & Evan R. Rees

  26. WRDM - Machine Learning Research, Pfizer, Berlin, Germany

    Djork-Arné Clevert

  27. Adapsyn Bioscience, Hamilton, Ontario, Canada

    Chris A. Dejong & Michael A. Skinnider

  28. Chemistry Department, University of St Andrews, St Andrews, UK

    Scarlet Ferrinho & Rebecca J. M. Goss

  29. Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

    Francesca Grisoni

  30. Centre for Living Technologies, Alliance TU/e, WUR, UU, UMC Utrecht, Utrecht, The Netherlands

    Francesca Grisoni

  31. Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland

    Albert Hofstetter

  32. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany

    Olga V. Kalinina, Rolf Müller & Anna K. H. Hirsch

  33. Drug Bioinformatics, Medical Faculty, Saarland University, Homburg, Germany

    Olga V. Kalinina

  34. Center for Bioinformatics, Saarland University, Saarbrücken, Germany

    Olga V. Kalinina & Andrea Volkamer

  35. Department of Chemistry, Scripps Research, FL, USA

    Satria A. Kautsar

  36. College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University Seoul, Goyang-si, Republic of Korea

    Hyunwoo Kim

  37. Center for Nuclear Energy in Agriculture, University of São Paulo, Piracicaba, Brazil

    Tiago F. Leao

  38. Center for Microbiology, VIB-KU Leuven, Heverlee, Belgium

    Joleen Masschelein

  39. Department of Biology, KU Leuven, Heverlee, Belgium

    Joleen Masschelein

  40. Institute of Pharmaceutical Biology and Biotechnology, University of Marburg, Marburg, Germany

    Raphael Reher

  41. Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

    Raphael Reher

  42. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Daniel Reker

  43. Duke Microbiome Center, Duke University, Durham, NC, USA

    Daniel Reker

  44. Laboratory of Artificial Chemical Intelligence, Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Philippe Schwaller

  45. Microsoft Research, Cambridge, UK

    Marwin Segler

  46. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada

    Michael A. Skinnider

  47. Department of Chemistry, Vanderbilt University, Nashville, TN, USA

    Allison S. Walker

  48. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA

    Allison S. Walker

  49. Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands

    Egon L. Willighagen

  50. European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridgeshire, UK

    Barbara Zdrazil

  51. Interfaculty Institute for Microbiology and Infection Medicine Tuebingen (IMIT), Institute for Bioinformatics and Medical Informatics (IBMI), University of Tuebingen, Tuebingen, Germany

    Nadine Ziemert

  52. Bonsai team, CRIStAL - Centre de Recherche en Informatique Signal et Automatique de Lille, Université de Lille, Villeneuve d’Ascq Cedex, France

    Pierre Guyomard

  53. In silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Andrea Volkamer

  54. Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA

    William H. Gerwick

  55. Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    Hyun Uk Kim

  56. Department of Pharmacy, Saarland University, Saarbrücken, Germany

    Rolf Müller & Anna K. H. Hirsch

  57. German Center for infection research (DZIF), Braunschweig, Germany

    Rolf Müller & Anna K. H. Hirsch

  58. Helmholtz International Lab for Anti-Infectives, Saarbrücken, Germany

    Rolf Müller & Anna K. H. Hirsch

  59. Netherlands Institute of Ecology, NIOO-KNAW, Wageningen, The Netherlands

    Gilles P. van Wezel

  60. Department of Environmental Microbiology, Eawag: Swiss Federal Institute for Aquatic Science and Technology, Dübendorf, Switzerland

    Serina L. Robinson

  61. Institute of Biology, Leiden University, Leiden, The Netherlands

    Marnix H. Medema

Authors
  1. Michael W. Mullowney
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  2. Katherine R. Duncan
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  3. Somayah S. Elsayed
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  4. Neha Garg
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  13. Eric J. N. Helfrich
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  14. Florian Huber
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  21. Mehdi A. Beniddir
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  28. Scarlet Ferrinho
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  33. Satria A. Kautsar
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  37. Evan R. Rees
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Contributions

M.W.M., S.S.E., D.M., B.R.T., M.G.G., S.L.-M., K.R., T.d.R., J.A.v.S., M.S., S.F., A.K.H.H., R.G.L., S.L.R. and M.H.M. researched data for the article. M.W.M., K.R.D., S.S.E., N.G., J.J.J.v.d.H., N.I.M., D.M., B.R.T., F.B., J.D., E.J.N.H., F.H., T.d.R., M.S., M.J.B., D.A.v.B., L.M.C., C.M.C., C.A.D., C.D., F.G., A.H., W.J., O.V.K., H.K., T.F.L., J.M., E.R.R., R.R., D.R., P.S., M.S., M.A.S., A.S.W., N.Z., R.J.M.G., A.V., W.H.G., R.M., G.P.v.W., G.J.P.v.W., A.K.H.H., R.L., S.L.R. and M.H.M. contributed substantially to discussion of the content. M.W.M., K.R.D., N.G., J.J.J.v.d.H., B.R.T., F.B., J.D., M.G.G., M.S., M.J.B., M.A.B., L.M.C., C.M.C., C.A.D., S.F., A.H., W.J., O.V.K., S.A.K., T.F.L., J.M., D.R., M.A.S., A.S.W., B.Z., N.Z., R.J.M.G., P.G., A.V., W.H.G., G.J.P.v.W., A.K.H.H., R.G.L., S.L.R. and M.H.M. wrote the article. M.W.M., K.R.D., S.S.E., N.G., J.J.J.v.d.H., N.I.M., D.M., B.R.T., F.B., K.B., E.J.N.H., F.H., T.d.R., M.J.B., L.M.C., C.M.C., D.-A.C., C.A.D., F.G., S.A.K., H.K., E.R.R., R.R., P.S., M.A.S., E.L.W., B.Z., W.H.G., H.U.K., R.M., G.P.v.W., G.J.P.v.W., A.K.H.H., R.G.L., S.L.R. and M.H.M. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Gerard J. P. van Westen, Anna K. H. Hirsch, Roger G. Linington, Serina L. Robinson or Marnix H. Medema.

Ethics declarations

Competing interests

J.J.J.v.d.H. is a member of the scientific advisory board of NAICONS Srl., Milan, Italy. C.A.D. is a founding member of Adapsyn Bioscience. M.A.S. is a consultant to Adapsyn Bioscience. M.H.M. is on the scientific advisory board of Hexagon Bio and co-founder of Design Pharmaceuticals. The other authors declare no competing interests.

Peer review

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Nature Reviews Drug Discovery thanks Hosein Mohimani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

National Database of Antibiotic Resistant Organisms (NDARO): https://www.ncbi.nlm.nih.gov/pathogens/antimicrobial-resistance/

RDKit: Open-Source Cheminformatics Software: http://www.rdkit.org/

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Mullowney, M.W., Duncan, K.R., Elsayed, S.S. et al. Artificial intelligence for natural product drug discovery. Nat Rev Drug Discov 22, 895–916 (2023). https://doi.org/10.1038/s41573-023-00774-7

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