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Natural products in drug discovery: advances and opportunities

Nature Reviews Drug Discovery volume 20, pages 200–216 (2021)Cite this article

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Abstract

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.

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Fig. 1: Outline of traditional bioactivity-guided isolation steps in natural product drug discovery.
Fig. 2: Applications of advanced analytical technologies empowering modern natural product-based drug discovery.
Fig. 3: Strategies for genome mining-driven discovery of natural products and natural product-like compounds.
Fig. 4: Application of advanced microbial culturing approaches to identify new natural products.
Fig. 5: Strategies to obtain natural product analogues with superior properties.

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Acknowledgements

This paper is affectionately dedicated in memory of Dr Mariola Macías (1984–2020) M.D., Ph.D. in Immunology, Emergency Physician at Hospital Punta Europa, Algeciras (Cadiz), Spain and active member of a research team working against SARS-CoV-2. An excellent professional and a better person. Her humanity, kindness, special and unmistakable smile, generosity, dedication and professionalism will never be forgotten. The authors are grateful to P. Kirkpatrick for his editorial contribution, which resulted in a greatly improved manuscript. A.G.A. acknowledges support from the Austrian Science Fund (FWF) project P25971-B23 (‘Improved cholesterol efflux by natural products’). R.B. acknowledges support by a grant from the Austrian Science Fund (FWF) P27505. V.B. acknowledges support by a grant from the Austrian Science Fund (FWF) P27682-B30. N.B. is recipient of an Australian Research Council DECRA Fellowship. A.C. and E.I. thank the Ministerio de Ciencia, Innovación y Universidades, Spain (Project AGL2017-89417-R) for support. M. Diederich is supported by the National Research Foundation (NRF) (grant number 019R1A2C1009231), by a grant from the MEST of Korea for Tumour Microenvironment Global Core Research Center (GCRC) (grant number NRF-2011-0030001), by the Creative-Pioneering Researchers Program through Seoul National University (Funding number: 370C-20160062), by the Brain Korea 21 (BK21) PLUS programme, by the ‘Recherche Cancer et Sang’ foundation, by the ‘Recherches Scientifiques Luxembourg’ association, by the ‘Een Häerz fir kriibskrank Kanner’ association, by the Action LIONS ‘Vaincre le Cancer’ association and by Télévie Luxembourg. The research work of A.T.D.-K. is funded by Cancer Research UK (C20953/A18644), the Biotechnology and Biological Sciences Research Council (BB/L01923X/1), Reata Pharmaceuticals, and Tenovus Scotland (T17/T14). B.L.F. acknowledges BMBF (TUNGER 036/FUCOFOOD) and AIF (AGEsense) for supporting his research. M.I.G. acknowledges financial support from the European Union’s Horizon 2020 research and innovation programme, project PlantaSYST (SGA No 739582 under FPA No. 664620) and the BG05M2OP001-1.003-001-C01 project, financed by the European Regional Development Fund through the ‘Science and Education for Smart Growth’ Operational Programme. K.M.G. is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515-10042) and the NIHR Southampton Biomedical Research Centre), the European Union (Erasmus+ Capacity-Building ENeA SEA Project and Seventh Framework Programme (FP7/2007-2013), projects EarlyNutrition and ODIN (grant agreements 289346 and 613977), the US National Institute On Ageing of the National Institutes of Health (award no. U24AG047867) and the UK ESRC and BBSRC (award no. ES/M00919X/1). Research in the laboratory of C.W.G. is supported by the Austrian Science Fund (FWF) through project P32109 and a NATVANTAGE grant 2019 by the Wilhelm Doerenkamp-Stiftung. A.K. acknowledges support by national funds through FCT-Foundation for Science and Technology of Portugal within the scope of UIDB/04423/2020 and UIDP/04423/2020. A.L. acknowledges HKBU SDF16-0603-P02 for supporting this research. F.A.M. acknowledges the support by Ministerio de Economia y Competitividad, Spain (project AGL2017-88083-R). A.M. acknowledges the support by a grant of the Romanian Ministry of Research and Innovation, CNCS – UEFISCDI, project number PN-III-P1-1.1-PD-2016-1900 – ‘PhytoSal’, within PNCDI III. G.P. acknowledges the support by NIH G12-MD007591, Kleberg Foundation and NIH R01-AG066749. M.R. acknowledges support by the Swiss National Science Foundation (Schweizerischer Nationalfonds, SNF), and by the Horizon 2020 programme of the European Union. J.M.R. acknowledges the support from the Austrian Science Fund (FWF: P24587), the Natvantage grant 2018 and the University of Vienna, Austria. G.L.R. acknowledges the group of Cellular and Molecular Nutrition (BJ-Lab) at the Institute of Food Sciences, National Research Council, Avellino, Italy. A.S.S. acknowledges the support by UIDB/00211/2020 with funding from FCT/MCTES through national funds. D.S. acknowledges the support by FWF S10711. D.S. is an Ingeborg Hochmair Professor at the University of Innsbruck. K.S.W. is supported by the National Centre for Research and Development (4/POLTUR-1/2016) and the National Science Centre (2017/27/B/NZ4/00917) and Medical University of Lublin, Poland. E.S.S. thanks Universidad Central de Chile, through Dirección de Investigación y Postgrado, for supporting this research. H. Stuppner acknowledges support by the Austrian Research Promotion Agency (FFG), the Austrian Science Fund (FWF) and the Horizon 2020 programme of the European Union (RISE, 691158). A.S. was granted by Instituto de Salud Carlos III, CIBEROBN (CB12/03/30038) and EU-COST Action (CA16112). M.W. acknowledges the support by DFG, BMBF, EU, CSC, DAAD, AvH and Land Baden Württemberg. J.L.W. is grateful to the Swiss National Science Foundation (SNF) for supporting its natural product metabolomics projects (grants nos. 310030E-164289, 31003A_163424 and 316030_164095). S.B.Z. acknowledges the support by University of Vienna, Vienna, Austria. M.H. acknowledges an EPSRC CASE Award (with Pukka Herbs Ltd, UK as industrial partner). I.B.-N. acknowledges the support of Competitivity Operational Program, 2014–2020, entitled ‘Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance’ — CANTEMIR, No. 35/01.09.2016, MySMIS 103375; project PNCDI III 2015-2020 entitled ‘Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers’ — ECHITAS, no. 29PFE/18.10.2018. This work was also funded by the Italian Ministry for University and Research (MIUR), grant PRIN: rot. 2017XYBP2R (to C.T.S).

Author information

Authors and Affiliations

  1. Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland

    Atanas G. Atanasov

  2. Department of Pharmacognosy, University of Vienna, Vienna, Austria

    Atanas G. Atanasov, Sergey B. Zotchev, Verena M. Dirsch & Judith M. Rollinger

  3. Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria

    Atanas G. Atanasov

  4. Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Vienna, Austria

    Atanas G. Atanasov

  5. Università degli Studi di Firenze, NEUROFARBA Dept, Sezione di Scienze Farmaceutiche, Florence, Italy

    Claudiu T. Supuran

  6. Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey

    Ilkay Erdogan Orhan

  7. Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Łodz, Poland

    Maciej Banach

  8. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Università degli Studi di Messina, Messina, Italy

    Davide Barreca

  9. Molecular Systems Biology (MOSYS), Department of Evolutionary and Functional Ecology, University of Vienna, Vienna, Austria

    Wolfram Weckwerth

  10. Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria

    Wolfram Weckwerth

  11. Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Graz, Austria

    Rudolf Bauer & Franz Bucar

  12. BioTechMed-Graz, Graz, Austria

    Rudolf Bauer

  13. Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel

    Edward A. Bayer

  14. Sami Labs Limited, 19/1, 19/2, First Main, Second Phase, Peenya Industrial Area, Bangalore, Karnataka, India

    Muhammed Majeed

  15. Sabinsa Corporation, East Windsor, NJ, USA

    Muhammed Majeed

  16. Sabinsa Corporation, Payson, UT, USA

    Muhammed Majeed

  17. Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA

    Anupam Bishayee

  18. Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Graz, Austria

    Valery Bochkov

  19. Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University of Innsbruck and Austrian Drug Screening Institute — ADSI, CCB — Center of Chemistry and Biomedicine, Innsbruck, Austria

    Günther K. Bonn

  20. Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia

    Nady Braidy

  21. Laboratory of Foodomics, Bioactivity and Food Analysis Department, Institute of Food Science Research CIAL (UAM-CSIC), Madrid, Spain

    Alejandro Cifuentes & Elena Ibanez

  22. Clinical Psychology Service, Health Department, Fondazione IRCCS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy

    Grazia D’Onofrio

  23. Evotec (UK) Ltd, Oxford, UK

    Michael Bodkin

  24. Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, South Korea

    Marc Diederich

  25. Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, UK

    Albena T. Dinkova-Kostova

  26. Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Albena T. Dinkova-Kostova

  27. Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany

    Thomas Efferth

  28. Cancer Biomarkers Working Group, Oujda, Morocco

    Khalid El Bairi

  29. International Natural Product Sciences Taskforce (INPST), Jastrzebiec, Poland

    Nicolas Arkells

  30. Department of Pharmacology, University of Cambridge, Cambridge, UK

    Tai-Ping Fan

  31. College of Life Sciences, Northwest University, Xi’an, China

    Tai-Ping Fan

  32. Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Bernd L. Fiebich

  33. Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Michael Freissmuth & Christian W. Gruber

  34. Laboratory of Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Plovdiv, Bulgaria

    Milen I. Georgiev

  35. Center of Plant Systems Biology and Biotechnology, Plovdiv, Bulgaria

    Milen I. Georgiev

  36. Research Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK

    Simon Gibbons

  37. MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Keith M. Godfrey

  38. UCB Pharma Ltd, Slough, UK

    Jag Heer

  39. Institute for Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

    Lukas A. Huber

  40. Austrian Drug Screening Institute-ADSI, Innsbruck, Austria

    Lukas A. Huber

  41. ICBAS-Instituto de Ciências Biomédicas Abel Salazar & CIIMAR, Universidade do Porto, Porto, Portugal

    Anake Kijjoa

  42. Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Warsaw, Poland

    Anna K. Kiss

  43. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

    Aiping Lu

  44. Allelopathy Group, Department of Organic Chemistry, Institute of Biomolecules (INBIO), Campus de Excelencia Internacional (ceiA3), School of Science, University of Cadiz, Cadiz, Spain

    Francisco A. Macias

  45. Kaiviti Consulting, LLC, Dallas, TX, USA

    Mark J. S. Miller

  46. Department of Pharmaceutical Botany, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Andrei Mocan

  47. Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University, Saarbrücken, Germany

    Rolf Müller

  48. German Centre for Infection Research (DZIF), Partner Site Hannover, Braunschweig, Germany

    Rolf Müller & Marc Stadler

  49. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

    Ferdinando Nicoletti

  50. Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA

    George Perry

  51. Department of Drug Science, University of Catania, Catania, Italy

    Valeria Pittalà

  52. Dipartimento di Farmacia, University of Salerno, Fisciano, Italy

    Luca Rastrelli

  53. Energy Metabolism Laboratory, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland

    Michael Ristow

  54. Institute of Food Sciences, National Research Council, Avellino, Italy

    Gian Luigi Russo

  55. National Institute for Agricultural and Veterinary Research (INIAV), Vila do Conde, Portugal

    Ana Sanches Silva

  56. Center for Study in Animal Science (CECA), ICETA, University of Porto, Porto, Portugal

    Ana Sanches Silva

  57. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, Salzburg, Austria

    Daniela Schuster

  58. Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria

    Daniela Schuster

  59. The NatPro Centre, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland

    Helen Sheridan

  60. Independent Laboratory of Natural Products Chemistry, Medical University of Lublin, Lublin, Poland

    Krystyna Skalicka-Woźniak

  61. Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens, Greece

    Leandros Skaltsounis

  62. Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain

    Eduardo Sobarzo-Sánchez

  63. Instituto de Investigación y Postgrado en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago, Chile

    Eduardo Sobarzo-Sánchez

  64. Janssen Pharmaceuticals Research & Development, San Diego, CA, USA

    David S. Bredt

  65. Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria

    Hermann Stuppner

  66. Research Group on Community Nutrition and Oxidative Stress, and Health Research Institute of the Balearic Islands (IdISBa), Department of Fundamental Biology and Health Sciences, University of Balearic Islands, Palma de Mallorca, Spain

    Antoni Sureda

  67. CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, Madrid, Spain

    Antoni Sureda

  68. Institute of Molecular Biology ‘Roumen Tsanev’, Department of Biochemical Pharmacology and Drug Design, Bulgarian Academy of Sciences, Sofia, Bulgaria

    Nikolay T. Tzvetkov

  69. Pharmaceutical Institute, University of Bonn, Bonn, Germany

    Nikolay T. Tzvetkov

  70. Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Italian National Council of Research, Bari, Italy

    Rosa Anna Vacca

  71. Inflammation Research Center, San Diego, CA, USA

    Bharat B. Aggarwal

  72. Department of Clinical Sciences, Università Politecnica delle Marche, Ancona, Italy

    Maurizio Battino & Francesca Giampieri

  73. International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, China

    Maurizio Battino, Jianbo Xiao & Maria Daglia

  74. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Francesca Giampieri

  75. College of Food Science and Technology, Northwest University, Xi’an, Shaanxi, China

    Francesca Giampieri

  76. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany

    Michael Wink

  77. School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland

    Jean-Luc Wolfender

  78. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU, Geneva, Switzerland

    Jean-Luc Wolfender

  79. Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo — Ourense Campus, Ourense, Spain

    Jianbo Xiao

  80. Oral and Maxillofacial Radiology, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China

    Andy Wai Kan Yeung

  81. Team Bio-PeroxIL, ‘Biochemistry of the Peroxisome, Inflammation and LipidMetabolism’ (EA7270)/University Bourgogne Franche-Comté/Inserm, Dijon, France

    Gérard Lizard

  82. Bionorica SE, Neumarkt/Oberpfalz, Germany

    Michael A. Popp

  83. Research Group ‘Pharmacognosy and Phytotherapy’, UCL School of Pharmacy, London, UK

    Michael Heinrich

  84. ‘Graduate Institute of Integrated Medicine, College of Chinese Medicine’, and ‘Chinese Medicine Research Center’, China Medical University, Taichung, Taiwan

    Michael Heinrich

  85. Research Center for Functional Genomics, Biomedicine and Translational Medicine, Institute of Doctoral Studies, ‘Iuliu Hatieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  86. Department of Experimental Pathology, ‘Prof. Dr. Ion Chiricuta’, The Oncology Institute, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  87. Helmholtz-Center for Infection Research, Department of Microbial Drugs, Braunschweig, Germany

    Marc Stadler

  88. Department of Pharmacy, University of Naples Federico II, Naples, Italy

    Maria Daglia

  89. Natural Products Laboratory, Institute of Biology, Leiden University, Leiden, Netherlands

    Robert Verpoorte

Authors
  1. Atanas G. Atanasov
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  2. Sergey B. Zotchev
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  3. Verena M. Dirsch
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  4. Claudiu T. Supuran
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Consortia

the International Natural Product Sciences Taskforce

  • Ilkay Erdogan Orhan
  • , Maciej Banach
  • , Judith M. Rollinger
  • , Davide Barreca
  • , Wolfram Weckwerth
  • , Rudolf Bauer
  • , Edward A. Bayer
  • , Muhammed Majeed
  • , Anupam Bishayee
  • , Valery Bochkov
  • , Günther K. Bonn
  • , Nady Braidy
  • , Franz Bucar
  • , Alejandro Cifuentes
  • , Grazia D’Onofrio
  • , Michael Bodkin
  • , Marc Diederich
  • , Albena T. Dinkova-Kostova
  • , Thomas Efferth
  • , Khalid El Bairi
  • , Nicolas Arkells
  • , Tai-Ping Fan
  • , Bernd L. Fiebich
  • , Michael Freissmuth
  • , Milen I. Georgiev
  • , Simon Gibbons
  • , Keith M. Godfrey
  • , Christian W. Gruber
  • , Jag Heer
  • , Lukas A. Huber
  • , Elena Ibanez
  • , Anake Kijjoa
  • , Anna K. Kiss
  • , Aiping Lu
  • , Francisco A. Macias
  • , Mark J. S. Miller
  • , Andrei Mocan
  • , Rolf Müller
  • , Ferdinando Nicoletti
  • , George Perry
  • , Valeria Pittalà
  • , Luca Rastrelli
  • , Michael Ristow
  • , Gian Luigi Russo
  • , Ana Sanches Silva
  • , Daniela Schuster
  • , Helen Sheridan
  • , Krystyna Skalicka-Woźniak
  • , Leandros Skaltsounis
  • , Eduardo Sobarzo-Sánchez
  • , David S. Bredt
  • , Hermann Stuppner
  • , Antoni Sureda
  • , Nikolay T. Tzvetkov
  • , Rosa Anna Vacca
  • , Bharat B. Aggarwal
  • , Maurizio Battino
  • , Francesca Giampieri
  • , Michael Wink
  • , Jean-Luc Wolfender
  • , Jianbo Xiao
  • , Andy Wai Kan Yeung
  • , Gérard Lizard
  • , Michael A. Popp
  • , Michael Heinrich
  • , Ioana Berindan-Neagoe
  • , Marc Stadler
  • , Maria Daglia
  •  & Robert Verpoorte

Corresponding authors

Correspondence to Atanas G. Atanasov or Claudiu T. Supuran.

Ethics declarations

Competing interests

A.G.A. is executive administrator of the International Natural Product Sciences Taskforce (INPST) and Digital Health and Patient Safety Platform (DHPSP). M. Banach has served on the speakers’ bureau of Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Novo-Nordisk, Novartis, Sanofi-Aventis, Servier and Valeant, has served as a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Novartis, Polfarmex, Resverlogix, Sanofi-Aventis, and has received grants from Amgen, Mylan, Sanofi and Valeant. R.B. collaborates with Bayer Consumer Health and Dr Willmar Schwabe GmbH & Co. KG, and is scientific advisory committee member of PuraPharm International (HK) Limited and ISURA. G.K.B. is a board member of Bionorica SE. M. Daglia has received consultancy honoraria from Pfizer Italia and Mylan for training courses for chemists, and is a member of the INPST board of directors. A.T.D.-K. is a member of the Scientific and Medical Advisory Board of Evgen Pharma plc. I.E.O. is Dean of Faculty of Pharmacy, Gazi University, Ankara, Turkey, member of the Traditional Chinese Medicine Experts Group in European Pharmacopeia, and principal member of Turkish Academy of Sciences (TUBA). B.L.F. is a member of the INPST Board of Directors and has received research funding from Dr Willmar Schwabe GmbH & Co. KG. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. C.W.G. is chairman of the scientific advisory board of Cyxone AB, SE. M.H.’s research group has received charitable donations from Dr Willmar Schwabe GmbH & Co. KG and recently completed a research project sponsored by Pukka Herbs, UK. A.L. is a member of the board of directors of Kaisa Health. M.J.S.M. is president of Kaiviti Consulting and consults for Gnosis by LeSaffre. F.N. is cofounder and shareholder of OncoNox and Aura Biopharm. G.P. is on the board of Neurotez and Neurotrope. M.R. serves as an adviser for the Nestlé Institute of Health Sciences. G.L.R. is a member of the board of directors of INPST. N.T.T. is Founder and CEO of NTZ Lab Ltd and advisory board member of INPST. M.W. collaborates with Finzelberg GmbH and Schwabe GmbH. J.L.W. collaborates with Nestlé and Firmenich. M.A.P. is CEO and owner of Bionorica SE. J.H. is an employee of and holds shares in UCB Pharma Ltd. M.M. is Founder and Chairman of Sami–Sabinsa Group of Companies. D.S.B. is an employee of Janssen R&D. M. Bodkin is an employee of Evotec (UK) Ltd.

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Related links

Dictionary of Natural Products: http://dnp.chemnetbase.com/faces/chemical/ChemicalSearch.xhtml

FDA botanical drug development guidance for industry: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/botanical-drug-development-guidance-industry

INPST: https://inpst.net/

Glossary

sp3 carbon atoms

Tetravalent carbon atoms forming single covalent bonds with other atoms within the molecular structure. A higher fraction of sp3 carbons within molecules is a descriptor that indicates more complex 3D structures.

Lipinski’s rule of five

This guideline for the likelihood of a compound having oral bioavailability is based on several characteristics containing the number 5. It predicts that a molecule is likely to have poor absorption or permeation if it has more than one of the following characteristics: there are >5 H-bond donors and >10 H-bond acceptors; the molecular weight is >500; or the partition coefficient LogP is >5. Notably, natural products were identified as common exceptions at the time of publication in 1997.

Dereplication

Pharmacological screening of natural product extracts yields hits potentially containing multiple natural products that need to be considered for further study to identify the bioactive compounds. Dereplication is the process of recognizing and excluding from further study such hit mixtures that contain already known bioactive compounds.

Phenotypic assays

Assays that rely on the ability of tested compounds to exert desired phenotypic changes in cells, isolated tissues, organs or animals. They offer a complementary strategy to target-based assays for identifying new potential drugs.

Phylogenomic approach

The use of genomic data to reveal evolutionary relationships. In the context of natural product drug discovery, the use of phylogenomics is based on the assumption that organisms that have closer evolutionary relationships are more likely to produce similar natural products.

Taxonomic distance

The distance of compared taxa on a constructed phylogenetic tree (also known as an evolutionary tree). Closer distance of compared taxa indicates a closer evolutionary relationship.

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Atanasov, A.G., Zotchev, S.B., Dirsch, V.M. et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20, 200–216 (2021). https://doi.org/10.1038/s41573-020-00114-z

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