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High impact technologies for natural products screening

  • Frank E. Koehn
Part of the Progress in Drug Research book series (PDR, volume 65)

Abstract

Natural products have historically been a rich source of lead molecules in drug discovery. However, natural products have been de-emphasized as high throughput screening resources in the recent past, in part because of difficulties in obtaining high quality natural products screening libraries, or in applying modern screening assays to these libraries. In addition, natural products programs based on screening of extract libraries, bioassay-guided isolation, structure elucidation and subsequent production scale-up are challenged to meet the rapid cycle times that are characteristic of the modern HTS approach. Fortunately, new technologies in mass spectrometry, NMR and other spectroscopic techniques can greatly facilitate the first components of the process — namely the efficient creation of high-quality natural products libraries, bimolecular target or cell-based screening, and early hit characterization.

The success of any high throughput screening campaign is dependent on the quality of the chemical library. The construction and maintenance of a high quality natural products library, whether based on microbial, plant, marine or other sources is a costly endeavor. The library itself may be composed of samples that are themselves mixtures — such as crude extracts, semi-pure mixtures or single purified natural products. Each of these library designs carries with it distinctive advantages and disadvantages. Crude extract libraries have lower resource requirements for sample preparation, but high requirements for identification of the bioactive constituents. Pre-fractionated libraries can be an effective strategy to alleviate interferences encountered with crude libraries, and may shorten the time needed to identify the active principle. Purified natural product libraries require substantial resources for preparation, but offer the advantage that the hit detection process is reduced to that of synthetic single component libraries. Whether the natural products library consists of crude or partially fractionated mixtures, the library contents should be profiled to identify the known components present — a process known as dereplication. The use of mass spectrometry and HPLC-mass spectrometry together with spectral databases is a powerful tool in the chemometric profiling of bio-sources for natural product production. High throughput, high sensitivity flow NMR is an emerging tool in this area as well. Whether by cell based or biomolecular target based assays, screening of natural product extract libraries continues to furnish novel lead molecules for further drug development, despite challenges in the analysis and prioritization of natural products hits.

Spectroscopic techniques are now being used to directly screen natural product and synthetic libraries. Mass spectrometry in the form of methods such as ESI-ICRFTMS, and FACS-MS as well as NMR methods such as SAR by NMR and STD-NMR have been utilized to effectively screen molecular libraries. Overall, emerging advances in mass spectrometry, NMR and other technologies are making it possible to overcome the challenges encountered in screening natural products libraries in today’s drug discovery environment. As we apply these technologies and develop them even further, we can look forward to increased impact of natural products in the HTS based drug discovery.

Keywords

Natural Product Saturation Transfer Difference Curr Opin Chem Biol Natural Product Extract Natural Product Library 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Steinmeyer A (2006) The hit-to-lead process at Schering AG: strategic aspects. ChemMed-Chem 1: 31–36Google Scholar
  2. 2.
    Baker D, Mocek U, Garr C (2000) Natural products vs. combinatorials: a case study. Special Publication — Royal Soc Chem 257: 66–72Google Scholar
  3. 3.
    Potterat O, Hamburger M (2006) Natural products in drug discovery — concepts and approaches for tracking bioactivity. Curr Org Chem 10: 899–920CrossRefGoogle Scholar
  4. 4.
    Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66: 1022–1037PubMedCrossRefGoogle Scholar
  5. 5.
    Silverman L, Campbell R, Broach JR (1998) New assay technologies for high-throughput screening. Curr Opin Chem Biol 2: 397–403PubMedCrossRefGoogle Scholar
  6. 6.
    Zaman GJR, Garritsen A, de Boer T, van Boeckel CAA (2003) Fluorescence assays for highthroughput screening of protein kinases. Combinatorial Chem High Throughput Screening 6: 313–320Google Scholar
  7. 7.
    Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP (2006) Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci USA 103: 11473–11478PubMedCrossRefGoogle Scholar
  8. 8.
    Fowler A, Swift D, Longman E, Acornley A, Hemsley P, Murray D, Unitt J, Dale I, Sullivan E, Coldwell M (2002) An evaluation of fluorescence polarization and lifetime discriminated polarization for high throughput screening of serine/threonine kinases. Anal Biochem 308: 223–231PubMedCrossRefGoogle Scholar
  9. 9.
    Turek-Etienne TC, Lei M, Terracciano JS, Langsdorf EF, Bryant RW, Hart RF, Horan AC (2004) Use of red-shifted dyes in a fluorescence polarization AKT kinase assay for detection of biological activity in natural product extracts. J Biomol Screening 9: 52–61CrossRefGoogle Scholar
  10. 10.
    Eldridge GR, Vervoort HC, Lee CM, Cremin PA, Williams CT, Hart SM, Goering MG, O’Neil-Johnson M, Zeng L (2002) High-throughput method for the production and analysis of large natural product libraries for drug discovery. Anal Chem 74: 3963–3971PubMedCrossRefGoogle Scholar
  11. 11.
    Abel U, Koch C, Speitling M, Hansske FG (2002) Modern methods to produce naturalproduct libraries. Curr Opin Chem Biol 6: 453–458PubMedCrossRefGoogle Scholar
  12. 12.
    Bindseil KU, Jakupovic J, Wolf D, Lavayre J, Leboul J, van der Pyl D (2001) Pure compound libraries; a new perspective for natural product based drug discovery. Drug Dis Today 6: 840–847CrossRefGoogle Scholar
  13. 13.
    Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nature Rev Drug Dis 4: 206–220CrossRefGoogle Scholar
  14. 14.
    Barrow RA (2005) Isolation of microbial natural products. Meth Biotech 20: 391–414Google Scholar
  15. 15.
    Henry MC, Yonker CR (2006) Supercritical fluid chromatography, pressurized liquid extraction, and supercritical fluid extraction. Anal Chem 78: 3909–3915PubMedCrossRefGoogle Scholar
  16. 16.
    Harrigan GG, Goetz GH (2005) Chemical and biological integrity in natural products screening. Combinatorial Chem High Throughput Screening 8: 529–534CrossRefGoogle Scholar
  17. 17.
    Yan B, Fang L, Irving M, Zhang S, Boldi AM, Woolard F, Johnson CR, Kshirsagar T, Figliozzi GM, Krueger CA et al (2003) Quality control in combinatorial chemistry: determination of the quantity, purity, and quantitative purity of compounds in combinatorial libraries. J Combinatorial Chem 5: 547–559CrossRefGoogle Scholar
  18. 18.
    Sadowski J, Kubinyi H (1998) A scoring scheme for discriminating between drugs and nondrugs. J Med Chem 41: 3325–3329PubMedCrossRefGoogle Scholar
  19. 19.
    Henkel T, Brunne RM, Muller H, Reichel F (1999) Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angewandte Chemie, Intl Ed 38: 643–647CrossRefGoogle Scholar
  20. 20.
    Newman DJ, Cragg GM, Kingston DGI (2003) Natural products as pharmaceuticals and sources for lead structures. Practice Med Chem (2nd Ed): 91–109Google Scholar
  21. 21.
    Feher M, Schmidt JM (2003) Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inform Comp Sci 43: 218–227CrossRefGoogle Scholar
  22. 22.
    Lee ML, Schneider G (2001) Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J Combinatorial Chem 3: 284–289CrossRefGoogle Scholar
  23. 23.
    Stahura FL, Godden JW, Xue L, Bajorath J (2000) Distinguishing between natural products and synthetic molecules by descriptor Shannon entropy analysis and binary QSAR calculations. J Chem Info Comp Sci 40: 1245–1252CrossRefGoogle Scholar
  24. 24.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 46: 3–26CrossRefGoogle Scholar
  25. 25.
    Malo N, Hanley JA, Cerquozzi S, Pelletier J, Nadon R (2006) Statistical practice in highthroughput screening data analysis. Nature Biotech 24: 167–175CrossRefGoogle Scholar
  26. 26.
    Lipinski CA (2001) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44: 235–249CrossRefGoogle Scholar
  27. 27.
    Osada H, Magae J, Watanabe C, Isono K (1988) Rapid screening method for inhibitors of protein kinase C. J Antibiotics 41: 925–931Google Scholar
  28. 28.
    Prudhomme M (2005) Staurosporines and structurally related indolocarbazoles as antitumor agents. Anticancer Agents Nat Prod 499–517Google Scholar
  29. 29.
    Kumar RA, Clark DS (2006) High-throughput screening of biocatalytic activity: applications in drug discovery. Curr Opin Chem Biol 10: 162–168PubMedCrossRefGoogle Scholar
  30. 30.
    Heilker R, Zemanova L, Valler MJ, Nienhaus GU (2005) Confocal fluorescence microscopy for high-throughput screening of G-protein coupled receptors. Curr Med Chem 12: 2551–2559PubMedCrossRefGoogle Scholar
  31. 31.
    Terstappen GC (2005) Ion channel screening technologies today. Drug Dis Today: Technologies 2: 133–140CrossRefGoogle Scholar
  32. 32.
    Croston GE (2002) Functional cell-based uHTS in chemical genomic drug discovery. Trends Biotech 20: 110–115CrossRefGoogle Scholar
  33. 33.
    Zheng X, Hu Y, Liu J, Ouyang K (2005) Screening of active compounds as neuromedin U2 receptor agonist from natural products. Bioorg Med Chem Lett 15: 4531–4535PubMedCrossRefGoogle Scholar
  34. 34.
    Henrich CJ, Bokesch HR, Dean M, Bates SE, Robey RW, Goncharova EI, Wilson JA, McMahon JB (2006) A high-throughput cell-based assay for inhibitors of ABCG2 activity. J Biomolecular Screening 11: 176–183CrossRefGoogle Scholar
  35. 35.
    Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R et al (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441: 358–361PubMedCrossRefGoogle Scholar
  36. 36.
    Ondeyka JG, Zink DL, Young K, Painter R, Kodali S, Galgoci A, Collado J, Tormo JR, Basilio A, Vicente F et al (2006) Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy. J Nat Prod 69: 377–380PubMedCrossRefGoogle Scholar
  37. 37.
    Yoo H-D, Cremin PA, Zeng L, Garo E, Williams CT, Lee CM, Goering MG, O’Neil-Johnson M, Eldridge GR, Hu JF (2005) Suaveolindole, a new mass-limited antibacterial indolosesquiterpene from Greenwayodendron suaveolens obtained via high-throughput natural products chemistry methods. J Nat Prod 68: 122–124PubMedCrossRefGoogle Scholar
  38. 38.
    Vogt A, Tamewitz A, Skoko J, Sikorski RP, Giuliano KA, Lazo JS (2005) The benzo[c] phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogenactivated protein kinase phosphatase-1. J Biol Chem 280: 19078–19086PubMedCrossRefGoogle Scholar
  39. 39.
    Summers MY, Leighton M, Liu D, Pong K, Graziani EI (2006) 3-normeridamycin: a potent non-immunosuppressive immunophilin ligand is neuroprotective in dopaminergic neurons. J Antibiotics 59: 184–189Google Scholar
  40. 40.
    Marion F, Williams DE, Patrick BO, Hollander I, Mallon R, Kim SC, Roll DM, Feldberg L, Van Soest R, Andersen RJ (2006) Liphagal, a selective inhibitor of pi3 kinase a isolated from the sponge aka coralliphaga: structure elucidation and biomimetic synthesis. Org Lett 8: 321–324PubMedCrossRefGoogle Scholar
  41. 41.
    Strege MA (1999) High-performance liquid chromatographic-electrospray ionization mass spectrometric analyses for the integration of natural products with modern highthroughput screening. J Chromatography B: Biomedical Sci Applications 725: 67–78CrossRefGoogle Scholar
  42. 42.
    Higgs RE, Zahn JA, Gygi JD, Hilton MD (2001) Rapid method to estimate the presence of secondary metabolites in microbial extracts. Applied Env Microbiol 67: 371–376CrossRefGoogle Scholar
  43. 43.
    Nielsen N-PV, Carstensen JM, Smedsgaard J (1998) Aligning of single and multiple wavelength chromatographic profiles for chemometric data analysis using correlation optimized warping. J Chromatography, A 805: 17–35CrossRefGoogle Scholar
  44. 44.
    van Nederkassel AM, Daszykowski M, Eilers PHC, Vander Heyden Y (2006) A comparison of three algorithms for chromatograms alignment. J Chromatography, A 1118: 199–210CrossRefGoogle Scholar
  45. 45.
    Tormo JR, Garcia JB (2005) Automated analyses of HPLC profiles of microbial extracts: a new tool for drug discovery screening. Nat Prod 57–75Google Scholar
  46. 46.
    Peake DA, Duckworth DC, Perun TJ, Scott WL, Kulanthaivel P, Strege MA (2005) Analytical and biological evaluation of high throughput screen actives using evaporative light scattering, chemiluminescent nitrogen detection, and accurate mass LC-MS-MS. Combinatorial Chem High Throughput Screening 8: 477–487CrossRefGoogle Scholar
  47. 47.
    Ganguly AK, Pramanik BN, Chen G, Shipkova PA (2002) Characterization of pharmaceuticals and natural products by electrospray ionization mass spectrometry. Practl Spectroscopy 32: 149–185Google Scholar
  48. 48.
    Fuellbeck M, Michalsky E, Dunkel M, Preissner R(2006) Natural products: sources and databases. Nat Prod Rep 23: 347–356CrossRefGoogle Scholar
  49. 49.
    Cremin PA, Zeng L (2002) High-throughput analysis of natural product compound libraries by parallel LC-MS evaporative light scattering detection. Anal Chem 74: 5492–5500PubMedCrossRefGoogle Scholar
  50. 50.
    Fredenhagen A, Derrien C, Gassmann E (2005) An MS/MS library on an ion-trap instrument for efficient dereplication of natural products. different fragmentation patterns for [M + H]+ and [M + Na]+ ions. J Nat Prod 68: 385–391PubMedCrossRefGoogle Scholar
  51. 51.
    Larsen TO, Smedsgaard J, Nielsen KF, Hansen ME, Frisvad JC (2005) Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat Prod Rep 22: 672–695PubMedCrossRefGoogle Scholar
  52. 52.
    Pauli GF, Jaki BU, Lankin DC (2005) Quantitative 1H NMR: development and potential of a method for natural products analysis. J Nat Prod 68: 133–149PubMedCrossRefGoogle Scholar
  53. 53.
    Bollard ME, Stanley EG, Lindon JC, Nicholson JK, Holmes E (2005) NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition. NMR in Biomedicine 18: 143–162PubMedCrossRefGoogle Scholar
  54. 54.
    Sehgal R, Nandave M, Ojha SK (2006) Natural products: leads for drug discovery and development. Pharma Rev 4: 40–44Google Scholar
  55. 55.
    Holmes E, Tang H, Wang Y, Seger C (2006) The assessment of plant metabolite profiles by NMR-based methodologies. Planta Medica 72: 771–785PubMedCrossRefGoogle Scholar
  56. 56.
    Pierens GK, Palframan ME, Tranter CJ, Carroll AR, Quinn RJ (2005) A robust clustering approach for NMR spectra of natural product extracts. Magnetic Resonance Chem 43: 359–365CrossRefGoogle Scholar
  57. 57.
    Jansma A, Chuan T, Albrecht RW, Olson DL, Peck TL, Geierstanger BH (2005) Automated microflow NMR: routine analysis of five-microliter samples. Anal Chem 77: 6509–6515PubMedCrossRefGoogle Scholar
  58. 58.
    Hu JF, Garo E, Yoo HD, Cremin PA, Zeng L, Goering MG, O’Neil-Johnson M, Eldridge GR (2005) Application of capillary-scale NMR for the structure determination of phytochemicals. Phytochem Anal 16: 127–133PubMedCrossRefGoogle Scholar
  59. 59.
    Taggi AE, Meinwald J, Schroeder FC (2004) A new approach to natural products discovery exemplified by the identification of sulfated nucleosides in spider venom. J Am Chem Soc 126: 10364–10369PubMedCrossRefGoogle Scholar
  60. 60.
    Zeng L, Cremin P, Lee C, O’Neil-Johnson M, Caporale L (2001) High throughput natural product chemistry for drug discovery. Abstracts of Papers, 221st ACS National Meeting, San Diego, CA, United States, April 1–5, 2001: MEDI-193Google Scholar
  61. 61.
    Schlotterbeck G, Ross A, Hochstrasser R, Senn H, Kuehn T, Marek D, Schett O (2002) High-resolution capillary tube NMR. A miniaturized 5-mL high-sensitivity TXI probe for mass-limited samples, off-line LC NMR, and HT NMR. Anal Chem 74: 4464–4471PubMedCrossRefGoogle Scholar
  62. 62.
    Laude DA Jr, Wilkins CL (1984) Direct-linked analytical scale high-performance liquid chromatography/nuclear magnetic resonance spectrometry. Anal Chem 56: 2471–2475CrossRefGoogle Scholar
  63. 63.
    Albert K (1999) Liquid chromatography-nuclear magnetic resonance spectroscopy. J Chromatography, A 856: 199–211CrossRefGoogle Scholar
  64. 64.
    Bringmann G, Wohlfarth M, Rischer H, Schlauer J, Brun R (2002) Extract screening by HPLC coupled to MS-MS, NMR, and CD: a dimeric and three monomeric naphthylisoquinoline alkaloids from Ancistrocladus griffithii. Phytochem 61: 195–204CrossRefGoogle Scholar
  65. 65.
    Jaroszewski JW (2005) Hyphenated NMR methods in natural products research, part 2: HPLC-SPE-NMR and other new trends in NMR hyphenation. Planta Medica 71: 795–802PubMedCrossRefGoogle Scholar
  66. 66.
    Jaroszewski JW (2005) Hyphenated NMR methods in natural products research, part 1: Direct hyphenation. Planta Medica 71: 691–700PubMedCrossRefGoogle Scholar
  67. 67.
    Exarchou V, Krucker M, van Beek TA, Vervoort J, Gerothanassis IP, Albert K (2005) LCNMR coupling technology: Recent advancements and applications in natural products analysis. Magnetic Resonance Chem 43: 681–687CrossRefGoogle Scholar
  68. 68.
    Bieri S, Varesio E, Veuthey J-L, Munoz O, Tseng L-H, Braumann U, Spraul M, Christen P (2006) Identification of isomeric tropane alkaloids from Schizanthus grahamii by HPLCNMR with loop storage and HPLC-UV-MS/SPE-NMR using a cryogenic flow probe. Phytochem Anal 17: 78–86PubMedCrossRefGoogle Scholar
  69. 69.
    Lambert M, Staerk D, Hansen SH, Jaroszewski JW (2005) HPLC-SPE-NMR hyphenation in natural products research: optimization of analysis of Croton membranaceus extract. Magnetic Resonance Chem 43: 771–775CrossRefGoogle Scholar
  70. 70.
    Smallcombe SH, Patt SL, Keifer PA(1995) WET solvent suppression and its applications to LC NMR and high-resolution NMR spectroscopy. J Magnetic Resonance, Series A 117: 295–303CrossRefGoogle Scholar
  71. 71.
    Spraul M, Freund AS, Nast RE, Withers RS, Maas WE, Corcoran O (2003) Advancing NMR sensitivity for LC-NMR-MS using a cryoflow probe: application to the analysis of acetaminophen metabolites in urine. Anal Chem 75: 1536–1541PubMedCrossRefGoogle Scholar
  72. 72.
    Putzbach K, Krucker M, Grynbaum MD, Hentschel P, Webb AG, Albert K (2005) Hyphenation of capillary high-performance liquid chromatography to microcoil magnetic resonance spectroscopy-determination of various carotenoids in a small-sized spinach sample. J Pharma Biomed Anal 38: 910–917CrossRefGoogle Scholar
  73. 73.
    Lewis RJ, Bernstein MA, Duncan SJ, Sleigh CJ (2005) A comparison of capillary-scale LCNMR with alternative techniques: Spectroscopic and practical considerations. Magnetic Resonance Chem 43: 783–789CrossRefGoogle Scholar
  74. 74.
    Seger C, Godejohann M, Tseng LH, Spraul M, Girtler A, Sturm S, Stuppner H (2005) LCDAD-MS/SPE-NMR hyphenation. a tool for the analysis of pharmaceutically used plant extracts: identification of isobaric iridoid glycoside regioisomers from Harpagophytum procumbens. Anal Chem 77: 878–885PubMedCrossRefGoogle Scholar
  75. 75.
    Lommen A, Godejohann M, Venema DP, Hollman PCH, Spraul M (2000) Application of directly coupled HPLC-NMR-MS to the identification and confirmation of Quercetin glycosides and Phloretin glycosides in apple peel. Anal Chem 72: 1793–1797PubMedCrossRefGoogle Scholar
  76. 76.
    Exarchou V, Godejohann M, Van Beek TA, Gerothanassis IP, Vervoort J (2003) LC-UVsolid-phase extraction-NMR-MS combined with a cryogenic flow probe and its application to the identification of compounds present in greek oregano. Anal Chem 75: 6288–6294PubMedCrossRefGoogle Scholar
  77. 77.
    Cummins LL, Chen S, Blyn LB, Sannes-Lowery KA, Drader JJ, Griffey RH, Hofstadler SA (2003) Multitarget affinity/specificity screening of natural products: finding and characterizing high-affinity ligands from complex mixtures by using high-performance mass spectrometry. J Nat Prod 66: 1186–1190PubMedCrossRefGoogle Scholar
  78. 78.
    Poulsen SA, Davis RA, Keys TG (2006) Screening a natural product-based combinatorial library using FTICR mass spectrometry. Bioorg Med Chem 14: 510–515PubMedCrossRefGoogle Scholar
  79. 79.
    Cheng X, Van Breemen RB (2005) Mass spectrometry-based screening for inhibitors of amyloid protein aggregation. Anal Chem 77: 7012–7015PubMedCrossRefGoogle Scholar
  80. 80.
    Moy FJ, Haraki K, Mobilio D, Walker G, Powers R, Tabei K, Tong H, Siegel MM (2001) MS/ NMR: A structure-based approach for discovering protein ligands and for drug design by coupling size exclusion chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy. Anal Chem 73: 571–581PubMedCrossRefGoogle Scholar
  81. 81.
    Schriemer DC, Bundle DR, Li L, Hindsgaul O (1999) Micro-scale frontal affinity chromatography with mass spectrometric detection: a new method for the screening of compound libraries. Angewandte Chemie, Intl Ed 37: 3383–3387CrossRefGoogle Scholar
  82. 82.
    Chan NWC, Lewis DF, Rosner PJ, Kelly MA, Schriemer DC (2003) Frontal affinity chromatography-mass spectrometry assay technology for multiple stages of drug discovery: applications of a chromatographic biosensor. Anal Biochem 319: 1–12PubMedCrossRefGoogle Scholar
  83. 83.
    Slon-Usakiewicz JJ, Ng W, Dai JR, Pasternak A, Redden PR (2005) Frontal affinity chromatography with MS detection (FAC-MS) in drug discovery. Drug Dis Today 10: 409–416CrossRefGoogle Scholar
  84. 84.
    Zhu L, Chen L, Luo H, Xu X (2003) Frontal affinity chromatography combined on-line with mass spectrometry: A tool for the binding study of different epidermal growth factor receptor inhibitors. Anal Chem 75: 6388–6393PubMedCrossRefGoogle Scholar
  85. 85.
    Fejzo J, Lepre C, Xie X (2003) Application of NMR screening in drug discovery. Curr Topics Med Chem 3: 81–97CrossRefGoogle Scholar
  86. 86.
    Carlomagno T (2005) Ligand-target interactions: what can we learn from NMR? Ann Rev Biophys Biomol Structure 34: 245–266, 242 platesCrossRefGoogle Scholar
  87. 87.
    Marchioro C, Davalli S, Provera S, Heller M, Ross A, Senn H (2003) Experiments in NMRbased screening. Methods Principles Med Chem 16: 321–340CrossRefGoogle Scholar
  88. 88.
    Shuker SB, Hajduk PJ, Meadows RP, Fesik SW (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274: 1531–1534PubMedCrossRefGoogle Scholar
  89. 89.
    Hajduk PJ, Augeri DJ, Mack J, Mendoza R, Yang J, Betz SF, Fesik SW (2000) NMR-based screening of proteins containing 13C-labeled methyl groups. J Am Chem Soc 122: 7898–7904CrossRefGoogle Scholar
  90. 90.
    Hajduk PJ, Gerfin T, Boehlen J-M, Haeberli M, Marek D, Fesik SW (1999) High-throughput nuclear magnetic resonance-based screening. J Med Chem 42: 2315–2317PubMedCrossRefGoogle Scholar
  91. 91.
    Shapiro MJ, Wareing JR (1999) High resolution NMR for screening ligand/protein binding. Curr Opin Drug Dis Dev 2: 396–400Google Scholar
  92. 92.
    Rees DC, Congreve M, Murray CW, Carr R (2004) Fragment-based lead discovery. Nature Rev Drug Dis 3: 660–672CrossRefGoogle Scholar
  93. 93.
    Mercier KA, Powers R (2005) Determining the optimal size of small molecule mixtures for high throughput NMR screening. J Biomolecular NMR 31: 243–258CrossRefGoogle Scholar
  94. 94.
    Mayer M, Meyer B (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angewandte Chemie, Intl Ed 38: 1784–1788CrossRefGoogle Scholar
  95. 95.
    Milton MJ, Williamson RT, Koehn FE (2006) Mapping the bound conformation and protein interactions of microtubule destabilizing peptides by STD-NMR spectroscopy. Bioorg Med Chem Lett 16: 4279–4282PubMedCrossRefGoogle Scholar
  96. 96.
    Carlomagno T, Blommers Marcel JJ, Meiler J, Jahnke W, Schupp T, Petersen F, Schinzer D, Altmann KH, Griesinger C (2003) The high-resolution solution structure of epothilone A bound to tubulin: an understanding of the structure-activity relationships for a powerful class of antitumor agents. Angewandte Chemie, Intl Ed 42: 2511–2515CrossRefGoogle Scholar
  97. 97.
    Politi M, Chavez MI, Canada FJ, Jimenez-Barbero J (2005) Screening by NMR: A new approach for the study of bioactive natural products? The example of Pleurotus ostreatus hot water extract. Eur J Org Chem 7: 1392–1396CrossRefGoogle Scholar
  98. 98.
    Chen A, Shapiro MJ (2000) NOE pumping as high-throughput method to determine compounds with binding affinity to macromolecules by NMR. J Am Chem Soc 122: 414–415CrossRefGoogle Scholar
  99. 99.
    Dalvit C, Pevarello P, Tato M, Veronesi M, Vulpetti A, Sundstrom M (2000) Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomolecular NMR 18: 65–68CrossRefGoogle Scholar
  100. 100.
    Johnson EC, Feher VA, Peng JW, Moore JM, Williamson JR (2003) Application of NMR SHAPES screening to an RNA target. J Am Chem Soc 125: 15724–15725PubMedCrossRefGoogle Scholar
  101. 101.
    Cohen Y, Avram L, Frish L (2005) Diffusion NMR spectroscopy in supramolecular and combinatorial chemistry: an old parameter — new insights. Angewandte Chemie, Intl Ed 44: 520–554CrossRefGoogle Scholar
  102. 102.
    Bleicher K, Lin M, Shapiro MJ, Wareing JR (1998) Diffusion edited NMR: screening compound mixtures by affinity NMR to detect binding ligands to vancomycin. J Org Chem 63: 8486–8490CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel (Switzerland) 2008

Authors and Affiliations

  • Frank E. Koehn
    • 1
  1. 1.Natural Products Discovery Research — Chemical and Screening SciencesWyeth ResearchPearl RiverUSA

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