Plant natural fragments, an innovative approach for drug discovery

Abstract

Plant natural products (PNP) (e.g., secondary vegetal metabolites and their derivatives) have been a productive source of active ingredients for the pharmaceutical industry. The High Throughput Screening of Plant Natural Products (PNP-HTS) with extracts or isolated compounds has shown to be time consuming, expensive, and not as successful as expected. Recently building upon the innovative fragment-based drug discovery (FBDD) a disruptive approach was developed based on PNP. The fragment approach involves elaboration and/or isolation of weakly binding small molecules with molecular weights between 150 and 250 Da. This method is fundamentally different from HTS in almost every aspect (i.e., size of the compound library, screening methods, and optimization steps from hit to lead). Due to their nature, vegetal natural fragments have unique three-dimensional (3D) properties, high Fsp3, low aromaticity, and large chemo-diversities which represent potential opportunities for developing novel drugs. Preliminary results using vegetal natural fragments appear to be a promising and emerging field which offers valuable prospects for developing new drugs.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

From David and Ausseil (2014)

Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

From Valenti et al. (2019)

Fig. 8
Fig. 9
Fig. 10

Adapted from Cherry and Mitchell (2008), Scott et al. (2012)

Fig. 11
Fig. 12
Fig. 13
Fig. 14

Abbreviations

ADMET:

Administration–distribution–metabolization–excretion–toxicology studies

FBDD:

Fragment based drug discovery

Fsp3 :

Ratio of sp3 carbon to the total number of carbon

HTS:

High throughput screening

MS:

Mass spectrometry

NMR:

Nuclear magnetic resonance

NP:

Natural products

PF:

Pierre Fabre

PFL:

Plant fragment library

PNP:

Plant natural products

SPR:

Surface plasmon resonance

References

  1. Agarwal G, Carcache PJB, Addo EM et al (2019) Current status and contemporary approaches to the discovery of antitumor agents from higher plants. Biotechnol Adv. https://doi.org/10.1016/j.biotechadv.2019.01.004

    Article  PubMed  PubMed Central  Google Scholar 

  2. Amirkia V, Heinrich M (2015) Natural products and drug discovery: a survey of stakeholders in industry and academia. Front Pharmacol 6:1–8

    Google Scholar 

  3. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM et al (2015) Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv 33:1582–1614

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Baell J, Walters MA (2014) Chemical con artists foil drug discovery. Nature 513:481–483

    CAS  PubMed  Google Scholar 

  5. Baker M (2013) Fragment-based lead discovery grows up. Nat Rev Drug Discov 12:5–7

    CAS  PubMed  Google Scholar 

  6. Baker M (2017) Fragment-based phenotypic screening is a hit. Nat Rev Drug Discov 16:225–226

    CAS  PubMed  Google Scholar 

  7. Barelier S, Pons J, Gehring K, Lancelin JM et al (2010) Ligand specificity in fragment-based drug design. J Med Chem 53:5256–5266

    CAS  PubMed  Google Scholar 

  8. Bathula SR, Akondi SM, Mainkar PS et al (2015) “Pruning of biomolecules and natural products (PBNP)”: an innovative paradigm in drug discovery. Org Biomol Chem 13:6432–6448

    CAS  PubMed  Google Scholar 

  9. Blundell TL (2017) Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry. IUCrJ 4:308–321

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Boufridi A, Quinn RJ (2017) Harnessing the properties of natural products. Annu Rev Pharmacol Toxicol 58:451–470

    PubMed  Google Scholar 

  11. Breinbauer R, Vetter IR, Waldmann H (2002) From protein domains to drug candidates: natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed 41:2878–2890

    CAS  Google Scholar 

  12. Brenner S, Lerner RA (1992) Encoded combinatorial chemistry. Proc Natl Acad Sci USA 89:5381–5383

    CAS  PubMed  Google Scholar 

  13. Brown DG, Boström J (2018) Where do recent small molecule clinical development candidates come from? J Med Chem 61:9442–9468

    CAS  PubMed  Google Scholar 

  14. Butler MS, Fontaine F, Cooper MA (2014) Natural product libraries: assembly, maintenance, and screening. Planta Med 80:1161–1170

    CAS  PubMed  Google Scholar 

  15. Carletti I, Massiot G, Debitus C (2011) Polyketide molecules as anticancer agents. PCT patent WO2011051380

  16. Chan DSH, Whitehouse AJ, Coyne AG et al (2017) Mass spectrometry for fragment screening. Essays Biochem 61:465–473

    PubMed  Google Scholar 

  17. Chanana S, Thomas CS, Braun DR et al (2017) Natural product discovery using planes of principal component analysis in R (PoPCAR). Metabolites 7(E34):1–12

    Google Scholar 

  18. Chavanieu A, Pugnière M (2016) Developments in SPR fragment screening. Expert Opin Drug Discov 11:489–499

    CAS  PubMed  Google Scholar 

  19. Chen Y, de Bruyns Kops C, Kirchmair J (2017) Data resources for the computer-guided discovery of bioactive natural products. J Chem Inf Model 57:2099–2111

    CAS  PubMed  Google Scholar 

  20. Chen Y, Gardia de Lomana M, Friedrich NO et al (2018) Characterization of the chemical space of known and readily obtainable natural products. J Chem Inf Model 58:1518–1532

    CAS  PubMed  Google Scholar 

  21. Cherry M, Mitchell T (2008) Introduction to fragment-based drug discovery. In: Zartler ER, Shapiro MJ (eds) Chapter 1 in fragment-based drug discovery: a practical approach. Wiley, New York

    Google Scholar 

  22. Chessari G, Woodhead AJ (2009) From fragment to clinical candidate: a historical perspective. Drug Discov Today 14:668–675

    CAS  PubMed  Google Scholar 

  23. Congreve M, Carr R, Murray C et al (2003) A ‘rule of three’ for fragment-based lead discovery. Drug Discov Today 8:876–877

    PubMed  Google Scholar 

  24. Congreve M, Chessari G, Tisi D et al (2008) Recent developments in fragment-based discovery. J Med Chem 51:3661–3680

    CAS  PubMed  Google Scholar 

  25. Crane EA, Gademann K (2016) Capturing biological activity in natural product fragments by chemical synthesis. Angew Chem Int Ed Engl 55:3882–3902

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Dalvit C, Vulpetti A (2018) Ligand-based fluorine NMR screening: principles and applications in drug discovery projects. J Med Chem. https://doi.org/10.1021/acs.jmedchem.8b0121(Just Accepted Manuscript Publication)

    Article  PubMed  Google Scholar 

  27. Dalvit C, Pevarello P, Tatò M, Veronesi M, Vulpetti A, Sundström M (2000) Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomol NMR 18:65–68

    CAS  PubMed  Google Scholar 

  28. David B (2018) New regulations for accessing plant biodiversity samples, what is ABS? Phytochem Rev 17:1211–1223

    CAS  Google Scholar 

  29. David B, Ausseil F (2014) High-throughput screening of vegetal natural substances. In: Hostettmann K, Chen S, Marston A, Stuppner H (eds) Handbook of chemical and biological plant analytical methods. Wiley, New York, pp 987–1010 (Chapter 44)

    Google Scholar 

  30. David B, Wolfender JL, Dias DA (2015) The pharmaceutical industry and natural products: historical status and new trends. Phytochem Rev 14:299–315

    CAS  Google Scholar 

  31. Davis AM, Plowright AT, Valeur E (2017) Directing evolution: the next revolution in drug discovery? Nat Rev Drug Discov 16:681–698

    CAS  PubMed  Google Scholar 

  32. Deyon-Jung L, Morice C, Chéry F et al (2016) Fragment pharmacophore-based in silico screening: a powerful approach for efficient lead discovery. Med Chem Commun 7:506–511

    CAS  Google Scholar 

  33. DiMasi JA, Grabowski HG, Hansen RW (2016) Innovation in the pharmaceutical industry: new estimates of R&D cost. J Health Econ 47:20–33

    PubMed  Google Scholar 

  34. DNP (2017) Dictionary of natural products on CD-ROM. Chapman and Hall, Boca Raton, FL

    Google Scholar 

  35. Erlanson DA, Jahnke W (2006) The concept of fragment-based drug discovery (chapter 1). In: Jahnke W, Erlanson DA, Mannhold R, Kubinyi H, Folkers G (eds) Fragment-based approaches in drug discovery. Methods and principles in medicinal chemistry. Wiley, New York, pp 3–10

    Google Scholar 

  36. Erlanson DA, Zartler (2019) Practical fragments. http://practicalfragments.blogspot.com/. Accessed 28 Jan 2019

  37. Erlanson DA, Fesik SW, Hubbard RE et al (2016) Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 15:605–619

    CAS  PubMed  Google Scholar 

  38. Fattori D (2004) Molecular recognition: the fragment approach in lead generation. Drug Discov Today 9:229–238

    CAS  PubMed  Google Scholar 

  39. Feher M, Schmidt JM (2003) Properties distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43:218–227

    CAS  PubMed  Google Scholar 

  40. Fischer M, Hubbard RE (2009) Fragment-based ligand discovery. Mol Interv 9:22–30

    CAS  PubMed  Google Scholar 

  41. Fuller N, Spadola L, Cowen S et al (2016) An improved model for fragment-based lead generation at AstraZeneca. Drug Discov Today 21:1272–1283

    PubMed  Google Scholar 

  42. Galloway WR, Spring DR (2011) Better leads come from diversity. Nature 470:43

    Google Scholar 

  43. Galloway WR, Isidro-Llobet A, Spring DR (2010) Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 1(80):1–13

    Google Scholar 

  44. Giannetti AM (2011) From experimental design to validated hits a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods Enzymol 493:169–218

    CAS  PubMed  Google Scholar 

  45. Gomes NGM, Pereira DM, Valentão P et al (2018) Hybrid MS/NMR methods on the prioritization of natural products: application in drug discovery. J Pharm Biomed Anal 147:234–249

    CAS  PubMed  Google Scholar 

  46. Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849–857

    CAS  PubMed  Google Scholar 

  47. Gossert AD, Jahnke W (2016) NMR in drug discovery: a practical guide to identification and validation of ligands interacting with biological macromolecules. Prog Nucl Magn Reson Spectrosc 97:82–125

    CAS  PubMed  Google Scholar 

  48. Gribbon P, Sewing A (2005) High-throughput drug discovery: what can we expect from HTS? Drug Discov Today 10:17–22

    PubMed  Google Scholar 

  49. Hajduk PJ (2006) Fragment-based drug design: how big is too big? J Med Chem 49:6972–6976

    CAS  PubMed  Google Scholar 

  50. Hajduk PJ (2011) Small molecules, great potential. Nature 470:42

    CAS  PubMed  Google Scholar 

  51. Hajduk PJ, Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6:211–219

    CAS  PubMed  Google Scholar 

  52. Hajduk PJ, Huth JR, Fesik SW (2005) Druggability indices for protein targets derived from NMR-based screening data. J Med Chem 48:2518–2525

    CAS  PubMed  Google Scholar 

  53. Hall RJ, Mortenson PN, Murray CW (2014) Efficient exploration of chemical space by fragment-based screening. Prog Biophys Mol Biol 116:82–91

    CAS  PubMed  Google Scholar 

  54. Hann MM, Leach AR, Harper G (2001) Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comput Sci 41:856–864

    CAS  PubMed  Google Scholar 

  55. Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov 14:111–129

    CAS  PubMed  Google Scholar 

  56. Henrich CJ, Beutler JA (2013) Matching the power of high throughput screening to the chemical diversity of natural products. Nat Prod Rep 30:1284–1298

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets: recent technological advances. Curr Opin Pharmacol 13:791–796

    CAS  PubMed  Google Scholar 

  58. Hiroaki H (2013) Recent applications of isotopic labeling for protein NMR in drug discovery. Expert Opin Drug Discov 8:523–536

    CAS  PubMed  Google Scholar 

  59. Huang R, Leung IKH (2019) Protein-small molecule interactions by WaterLOGSY. Methods Enzymol 615:477–500

    CAS  PubMed  Google Scholar 

  60. Hubbard RE (1997) Can drugs be designed? Curr Opin Biotechnol 8:696–700

    CAS  PubMed  Google Scholar 

  61. Hubbard RE (2005) 3D structure and the drug-discovery process. Mol Biosyst 1:391–406

    Google Scholar 

  62. Hubbard RE (2008) Fragment approaches in structure-based drug discovery. J Synchrotron Radiat 15:227–230

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hubbard RE (2015) The fragment based lead discovery (chapter 5). In: Davis A, Ward SE (eds) The handbook of medicinal chemistry: principles and practices. Wiley, New York, pp 122–153

    Google Scholar 

  64. Hubbard RE (2016) The role of fragment-based discovery in lead finding. In: Erlanson DA, Jahnke W (eds) Chapter 1 in fragment-based discovery. Wiley, New York, pp 3–36

    Google Scholar 

  65. Hubbard RE, Murray JB (2011) Experiences in fragment-based lead discovery. Methods Enzymol 493:509–531

    CAS  PubMed  Google Scholar 

  66. Huber W, Mueller F (2006) Biomolecular interaction analysis in drug discovery using surface plasmon resonance technology. Curr Pharm Des 12:3999–4021

    CAS  PubMed  Google Scholar 

  67. Jencks WP (1981) On the attribution and additivity of binding energies. Proc Natl Acad Sci USA 78:4046–4050

    CAS  PubMed  Google Scholar 

  68. Johnson CN, Erlanson DA, Jahnke W et al (2018) Fragment-to-lead medicinal chemistry publications in 2016. J Med Chem 61:1774–1784

    CAS  PubMed  Google Scholar 

  69. Keserű GM, Hann MM (2017) What is the future for fragment-based drug discovery? Future Med Chem 9:1457–1460

    PubMed  Google Scholar 

  70. Keserű GM, Erlanson DA, Ferenczy GG et al (2016) Design principles for fragment libraries: maximizing the value of learnings from pharma fragment-based drug discovery (FBDD) programs for use in academia. J Med Chem 59:8189–8206

    PubMed  Google Scholar 

  71. Kutchukian PS, Wassermann AM, Lindvall MK et al (2015) Large scale meta-analysis of fragment-base screening campaigns: privileged fragments and complementary technologies. J Biomol Screen 20:588–596

    CAS  PubMed  Google Scholar 

  72. Lamoree B, Hubbard RE (2017) Current perspectives in fragment-based lead discovery (FBLD). Essays Biochem 61:453–464

    PubMed  PubMed Central  Google Scholar 

  73. Lanz J, Riedl R (2015) Merging allosteric and active site binding motifs: de novo generation of target selectivity and potency via natural-product-derived fragments. Chem Med Chem 10:451–454

    CAS  PubMed  Google Scholar 

  74. Leach AR, Hann MM, Burrows JN et al (2006) Fragment screening: an introduction. Mol Biosyst 2:430–446

    PubMed  Google Scholar 

  75. Lipinski C, Hopkins A (2004) Navigating chemical space for biology and medicine. Nature 432:855–861

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Long C, Sauleau P, David B et al (2003) Bioactive flavonoids of Tanacetum parthenium revisited. Phytochemistry 64:567–569

    CAS  PubMed  Google Scholar 

  77. Long C, Beck J, Cantagrel F et al (2012) Proteasome inhibitors from Neoboutonia melleri. J Nat Prod 75:34–47

    CAS  PubMed  Google Scholar 

  78. Lovering F, Bikker J, Humblet C (2009) Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem 32:6752–6756

    Google Scholar 

  79. Maybridge (2019) The Maybridge Ro3 2500 Diversity Fragment Library. https://www.maybridge.com/portal/alias__Rainbow/lang__en/tabID__230/DesktopDefault.aspx. Cited 14 Mar 2019

  80. Mayer M, Meyer B (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew Chem Int Ed Engl 38:1784–1788

    CAS  PubMed  Google Scholar 

  81. Montfort RLM, Workman P (2017) Structure-based drug design: aiming for a perfect fit. Essays Biochem 61:431–437

    PubMed  PubMed Central  Google Scholar 

  82. Morgan P, Brown DG, Lennard S et al (2018) Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Discov 17:167–181

    CAS  PubMed  Google Scholar 

  83. Morley AD, Pugliese A, Birchall K et al (2013) Fragment-based hit identification: thinking in 3D. Drug Discov Today 18:1221–1227

    PubMed  Google Scholar 

  84. Mullin R (2004) Drug discovery: as high-throughput screening draws fire, researchers leverage science to put automation into perspective. Chem Eng News 82:23–32

    Google Scholar 

  85. Murray CW, Rees D (2009) The rise of fragment-based drug discovery. Nat Chem 1:187–192

    CAS  PubMed  Google Scholar 

  86. Murray CW, Verdonck ML, Rees DC (2012) Experiences in fragment-based drug discovery. Trends Pharm Sci 33:224–232

    CAS  PubMed  Google Scholar 

  87. Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661

    CAS  Google Scholar 

  88. Oganesyan I, Lento C, Wilson DJ (2018) Contemporary hydrogen deuterium exchange mass spectrometry. Methods 144:27–42

    CAS  PubMed  Google Scholar 

  89. Oprea TI (2002) Current trends in lead discovery: are we looking for the appropriate properties? J Comput Aided Mol Des 16:325–334

    CAS  PubMed  Google Scholar 

  90. Over B, Wetzel S, Grütter C et al (2013) Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem 5:21–28

    CAS  PubMed  Google Scholar 

  91. Pahl A, Waldmann H, Kumar K (2017) Exploring natural product fragments for drug and probe discovery. Chimia 71:653–660

    CAS  PubMed  Google Scholar 

  92. Pascolutti M, Quinn RJ (2014) Natural products as lead structures: chemical transformations to create lead-like libraries. Drug Discov Today 19:215–221

    CAS  PubMed  Google Scholar 

  93. Pascolutti M, Campitelli M, Nguyen B et al (2015) Capturing nature’s diversity. PLoS ONE 10(4):e0120942

    PubMed  PubMed Central  Google Scholar 

  94. Paterson I, Anderson EA (2005) The renaissance of natural products as drug candidates. Science 310:451–453

    PubMed  Google Scholar 

  95. Pedro L, Quinn RJ (2016) Native mass spectrometry in fragment-based drug discovery. Molecules 21:984–999

    PubMed Central  Google Scholar 

  96. Pouny I, Batut M, Vendier L et al (2014) Cytisine-like alkaloids from Ormosia hosiei Hemsl. & E.H. Wilson. Phytochemistry 107:97–101

    CAS  PubMed  Google Scholar 

  97. Prescher H, Koch G, Schuhmann T, Ertl P (2017) Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products. Bioorg Med Chem 25:921–925

    CAS  PubMed  Google Scholar 

  98. Price AJ, Howard S, Cons BD (2017) Fragment-based drug discovery and its application to challenging drug targets. Essays Biochem 61:475–484

    PubMed  Google Scholar 

  99. Pye CR, Bertin MJ, Lokey RS et al (2017) Retrospective analysis of natural products provides insights for the future discovery trends. Proc Natl Acad Sci USA 114:5601–5606

    CAS  PubMed  Google Scholar 

  100. Rachman MM, Barril X, Hubbard RE (2018) Predicting how drug molecules bind to their protein targets. Curr Opin Pharmacol 42:34–39

    CAS  PubMed  Google Scholar 

  101. Rees DC, Congreve M, Murray CW et al (2004) Fragment-based lead discovery. Nat Rev Drug Discov 3:660–672

    CAS  PubMed  Google Scholar 

  102. Renaud JP, Chung CW, Danielson UH et al (2016) Biophysics in drug discovery: impact, challenges and opportunities. Nat Rev Drug Discov 15:679–698

    CAS  PubMed  Google Scholar 

  103. Rodrigues T, Reker D, Kunze J et al (2015) Revealing the macromolecular targets of fragment-like natural products. Angew Chem Int Ed Engl 127:10662–10666

    Google Scholar 

  104. Rogers D, Hahn M (2010) Extended-connectivity fingerprints. J Chem Inf Model 50:742–754

    CAS  PubMed  Google Scholar 

  105. Romasanta AKS, van der Sijde P, Hellsten I et al (2018) When fragments link: a bibliometric perspective on the development of fragment-based drug discovery. Drug Discov Today 23:1596–1609

    CAS  PubMed  Google Scholar 

  106. Roughley SD, Hubbard RE (2011) How well can fragments explore accessed chemical space? A case study from heat shock protein 90. J Med Chem 54:3989–4005

    CAS  PubMed  Google Scholar 

  107. Scannel JW, Blanckley A, Boldon H et al (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11:191–200

    Google Scholar 

  108. Schulz MN, Hubbard RE (2009) Recent progress in fragment-based lead discovery. Curr Opin Pharmacol 9:615–621

    CAS  PubMed  Google Scholar 

  109. Schulz MN, Landström J, Bright K et al (2011) Design of a fragment library that maximally represents available chemical space. J Comput Aided Mol Des 25:611–620

    CAS  PubMed  Google Scholar 

  110. Scott DE, Coyne AG, Hudson SA et al (2012) Fragment-based approaches to drug discovery and chemical biology. Biochemistry 51:4990–5003

    CAS  PubMed  Google Scholar 

  111. Sharma S, Karri K, Thapa I et al (2016) Identifying enriched drug fragments as possible candidates for metabolic engineering. BMC Med Genom 9(Suppl 2):167–177

    Google Scholar 

  112. Shoichet BK (2013) Nature’s pieces. Nat Chem 5:9–10

    CAS  PubMed  Google Scholar 

  113. Shuker SB, Hajduk PJ, Meadows RP et al (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274:1531–1534

    CAS  PubMed  Google Scholar 

  114. Siegel MG, Vieth M (2007) Drugs in other drugs: a new look at drugs as fragments. Drug Discov Today 12:71–79

    CAS  PubMed  Google Scholar 

  115. Speck-Planche A (2018) Recent advances in fragment-based computational drug design: tackling simultaneous targets/biological effects. Future Med Chem 10:2021–2024

    CAS  PubMed  Google Scholar 

  116. Sugiki T, Furuita K, Fujiwara T, Kojima C (2018) Current NMR techniques for structure-based drug discovery. Molecules 23:E148. https://doi.org/10.1007/s10930-018-9797-3

    CAS  Article  PubMed  Google Scholar 

  117. Valenti D, Hristeva S, Tzalis D et al (2019) Clinical candidates modulating protein–protein interactions: the fragment-based experience. Eur J Med Chem 167:76–95

    CAS  PubMed  Google Scholar 

  118. Veber DF, Johnson SR, Cheng HY et al (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623

    CAS  PubMed  Google Scholar 

  119. Velvadapu V, Farmer BT, Reitz AB (2015) Fragment-based drug discovery. In: Wermuth C, Aldous D, Raboisson P, Rognan D (eds) Chapter 7 in the practice of medicinal chemistry, 4th edn. Academic Press, London

    Google Scholar 

  120. Verlinde CL, Rudenko G, Hol WG (1992) In search of new lead compounds for trypanosomiasis drug design: a protein structure-based linked-fragment approach. J Comput Aided Mol Des 6:131–147

    CAS  PubMed  Google Scholar 

  121. Viegas A, Manso J, Nobrega FL et al (2011) Saturation-transfer difference (STD) MMR: a simple and fast method for ligand screening and characterization of protein binding. J Chem Educ 88:990–994

    CAS  Google Scholar 

  122. Vivat Hannah V, Atmanene C, Zeyer D, Van Dorsselaer A, Sanglier-Cianférani S (2010) Native MS: an ‘ESI’ way to support structure- and fragment-based drug discovery. Future Med Chem 2:35–50

    PubMed  Google Scholar 

  123. Vu H, Roullier C, Campitelli M et al (2013) Plasmodium gametocyte inhibition identified from a natural-product-based fragment library. ACS Chem Biol 8:2654–2659

    CAS  PubMed  Google Scholar 

  124. Vu H, Pedro L, Mak T et al (2018) Fragment-based screening of a natural product library against 62 potential malaria drug targets employing native mass spectrometry. ACS Infect Dis 4:431–444

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Williams G, Ferenczy GG, Ulander J et al (2017) Binding thermodynamics discriminates fragments from druglike compounds: a thermodynamic description of fragment-based drug discovery. Drug Discov Today 22:681–689

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Bruno David.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

David, B., Grondin, A., Schambel, P. et al. Plant natural fragments, an innovative approach for drug discovery. Phytochem Rev 19, 1141–1156 (2020). https://doi.org/10.1007/s11101-019-09612-4

Download citation

Keywords

  • Fragment
  • Drug discovery
  • Fragment-based drug discovery
  • Ligand efficiency