Advertisement

Advances in Nuclear Magnetic Resonance for Drug Discovery

  • Laurel O. SillerudEmail author
  • Richard S. Larson
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 910)

Abstract

Nuclear Magnetic Resonance (NMR) techniques are widely used in the drug discovery process. The primary feature exploited in these investigations is the large difference in mass between drugs and receptors (usually proteins) and the effect this has on the rotational or translational correlation times for drugs bound to their targets. Many NMR parameters, such as the diffusion coefficient, spin diffusion, nuclear Overhauser enhancement, and transverse and longitudinal relaxation times, are strong functions of either the overall tumbling or translation of molecules in solution. This has led to the development of a wide variety of NMR techniques applicable to the elucidation of protein and nucleic acid structure in solution, the screening of drug candidates for binding to a target of choice, and the study of the conformational changes which occur in a target upon drug binding. High-throughput screening by NMR methods has recently received a boost from the introduction of sophisticated computational techniques for reducing the time needed for the acquisition of the primary NMR data for multidimensional studies.

Key words

Nuclear magnetic resonance Diffusion Nuclear Overhauser enhancement Correlation times Chemical shift Nuclear spin Receptor Drug candidate trNOESY Saturations transfer difference LOGSY Structure–activity relationships TROSY Residual dipolar couplings HSQC Multiquantum 

References

  1. 1.
    Pochapsky SS, Pochapsky TC (2001) Nuclear magnetic resonance as a tool in drug discovery, metabolism and disposition. Curr Top Med Chem 1:427–441PubMedGoogle Scholar
  2. 2.
    Johnson MA, Pinto BM (2004) NMR spectroscopic and molecular modeling studies of protein-carbohydrate and protein-peptide interactions. Carbohydr Res 339:907–928PubMedGoogle Scholar
  3. 3.
    Chen A, Shapiro MJ (1999) Affinity NMR. Anal Chem 71:669A–675APubMedGoogle Scholar
  4. 4.
    Jahnke W (2007) Perspectives of biomolecular NMR in drug discovery: the blessing and curse of versatility. J Biomol NMR 39:87–90PubMedGoogle Scholar
  5. 5.
    Lepre CA, Moore JM, Peng JW (2004) Theory and applications of NMR-based screening in pharmaceutical research. Chem Rev 104:3641–3676PubMedGoogle Scholar
  6. 6.
    De Clercq E (2002) Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1:13–25PubMedGoogle Scholar
  7. 7.
    Stejskal EO, Tanner JE (1965) Spin diffusion measurements: spin echoes in the presence of a time-dependent field gradient. J Chem Phys 42:288–292Google Scholar
  8. 8.
    Luo RS, Liu ML, Mao XA (1999) NMR diffusion and relaxation study of drug-protein interaction. Spectrochim Acta A Mol Biomol Spectrosc 55A:1897–1901PubMedGoogle Scholar
  9. 9.
    Utsumi H, Seki H, Yamaguchi K, Tashiro M (2003) Segment identification of a ligand binding with a protein receptor using multidimensional T1rho-, diffusion-filtered and diffusion-ordered NOESY experiments. Anal Sci 19:1441–1443PubMedGoogle Scholar
  10. 10.
    Lucas LH, Yan J, Larive CK, Zartler ER, Shapiro MJ (2003) Transferred nuclear overhauser effect in nuclear magnetic resonance diffusion measurements of ligand-protein binding. Anal Chem 75:627–634PubMedGoogle Scholar
  11. 11.
    Ni F, Zhu Y (1994) Accounting for ligand-protein interactions in the relaxation-matrix analysis of transferred nuclear Overhauser effects. J Magn Reson B 103:180–184PubMedGoogle Scholar
  12. 12.
    Pervushin K, Riek R, Wider G, Wuthrich K (1997) Attenuated T2 relaxation by mutual cancellation of dipole-dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution. Proc Natl Acad Sci USA 94:12366–12371PubMedGoogle Scholar
  13. 13.
    Fernandez C, Wider G (2003) TROSY in NMR studies of the structure and function of large biological macromolecules Curr. Curr Opin Struct Biol 13:570–580PubMedGoogle Scholar
  14. 14.
    Pellecchia M, Meininger D, Shen AL, Jack R, Kasper CB, Sem DS (2001) SEA-TROSY (solvent exposed amides with TROSY): a method to resolve the problem of spectral overlap in very large proteins. J Am Chem Soc 123:4633–4634PubMedGoogle Scholar
  15. 15.
    Lin D, Sze KH, Cui Y, Zhu G (2002) Clean SEA-HSQC: a method to map solvent exposed amides in large non-deuterated proteins with gradient-enhanced HSQC. J Biomol NMR 23:317–322PubMedGoogle Scholar
  16. 16.
    Kim S, Szyperski T (2004) GFT NMR experiments for polypeptide backbone and 13Cbeta chemical shift assignment. J Biomol NMR 28:117–130PubMedGoogle Scholar
  17. 17.
    Frydman L, Scherf T, Lupulescu A (2002) The acquisition of multidimensional NMR spectra within a single scan. Proc Natl Acad Sci USA 99:15858–15862PubMedGoogle Scholar
  18. 18.
    Weigelt J, Wikstrom M, Schultz J, van Dongen MJ (2002) Site-selective labeling strategies for screening by NMR. Comb Chem High Throughput Screen 5:623–630PubMedGoogle Scholar
  19. 19.
    Tolman JR, Flanagan JM, Kennedy MA, Prestegard JH (1995) Nuclear magnetic dipole interactions in field-oriented proteins: information for structure determination in solution Proc. Proc Natl Acad Sci USA 92:9279–9283PubMedGoogle Scholar
  20. 20.
    Skrynnikov NR, Goto NK, Yang D, Choy WY, Tolman JR, Mueller GA, Kay LE (2000) Orienting domains in proteins using dipolar couplings measured by liquid-state NMR: differences in solution and crystal forms of maltodextrin binding protein loaded with beta-cyclodextrin. J Mol Biol 295:1265–1273PubMedGoogle Scholar
  21. 21.
    Shuker SB, Hajduk PJ, Meadows RP, Fesik SW (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274:1531–1534PubMedGoogle Scholar
  22. 22.
    Hajduk PJ, Sheppard G, Nettesheim DG, Olejniczak ET, Shuker SB, Meadows RP, Steinman DH, Carrera GM Jr, Marcotte PA, Severin J, Walter K, Smith H, Buggins E, Simmer R, Holzman TF, Morgan DW, Davidsen SK, Summers JB, Fesik SW (1997) Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 119:5818–5827Google Scholar
  23. 23.
    Lin M, Shapiro MJ (1996) Mixture analysis in combinatorial chemistry. Application of Diffusion-Resolved NMR Spectroscopy. J Org Chem 61:7617–7619PubMedGoogle Scholar
  24. 24.
    Hajduk PJ, Dinges J, Miknis GF, Merlock M, Middleton T, Kempf DJ, Egan DA, Walter KA, Robins TS, Shuker SB, Holzman TF, Fesik SW (1997) NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein. J Med Chem 40:3144–3150PubMedGoogle Scholar
  25. 25.
    Danielsson J, Jarvet J, Damberg P, Graslund A (2004) Two-site binding of beta-cyclodextrin to the Alzheimer Abeta(1-40) peptide measured with combined PFG-NMR diffusion and induced chemical shifts. Biochemistry 43:6261–6269PubMedGoogle Scholar
  26. 26.
    Pelta MD, Morris GA, Stchedroff MJ, Hammond SJ (2002) A one-shot sequence for high-resolution diffusion-ordered spectroscopy. Magn Reson Chem 40:S147–S152Google Scholar
  27. 27.
    Derrick TS, McCord EF, Larive CK (2002) Analysis of protein/ligand interactions with NMR diffusion measurements: the importance of eliminating the protein background. J Magn Reson 155:217–225PubMedGoogle Scholar
  28. 28.
    Lin M, Shapiro MJ, Wareing JR (1997) Diffusion-edited NMR-affinity NMR for direct observation of molecular interactions. J Am Chem Soc 119:5249–5250Google Scholar
  29. 29.
    Ponstingl H, Otting G (1997) NMR assignments, secondary structure and hydration of oxidized Escherichia coli flavodoxin Eur. J Biochem 244:384–399Google Scholar
  30. 30.
    Gonnella N, Lin M, Shapiro MJ, Wareing JR, Zhang X (1998) Isotope-filtered affinity NMR. J Magn Reson 131:336–338PubMedGoogle Scholar
  31. 31.
    Tillett ML, Horsfield MA, Lian LY, Norwood TJ (1999) Protein-ligand interactions ­measured by 15N-filtered diffusion experiments. J Biomol NMR 13:223–232PubMedGoogle Scholar
  32. 32.
    Yuan P, Marshall VP, Petzold GL, Poorman RA, Stockman BJ (1999) Dynamics of stromelysin/inhibitor interactions studied by 15N NMR relaxation measurements: ­comparison of ligand binding to the S1-S3 and S′1-S′3 subsites. J Biomol NMR 15:55–64PubMedGoogle Scholar
  33. 33.
    Clore GM, Gronenborn AM (1982) Theory and applications of the transferred nuclear Overhauser effect to the study of the conformations of small ligands bound to proteins. J Magn Reson 48:402–417Google Scholar
  34. 34.
    Campbell AP, Sykes BD (1993) The two-dimensional transferred nuclear Overhauser effect: theory and practice. Annu Rev Biophys Biomol Struct 22:99–122PubMedGoogle Scholar
  35. 35.
    Ni F (2004) Recent developments in transferred NOE methods. Prog Nucl Magn Reson Spectrosc 26:517–606Google Scholar
  36. 36.
    Meyer B, Weimar T, Peters T (1997) Screening mixtures for biological activity by NMR. Eur J Biochem 246:705–709PubMedGoogle Scholar
  37. 37.
    Henrichson D, Ernst B, Magnani JL, Wang WT, Meyer B, Peters T (1999) Bioaffinity NMR spectroscopy: Identification of an E-selectin antagonist in a substance mixture by transfer NOE. Angew Chem Int Ed 38:98–102Google Scholar
  38. 38.
    Herfurth L, Weimar T, Peters T (2000) Application of 3D-TOCSY-trNOESY for the assignment of bioactive ligands from mixtures. Angew Chem Int Ed Engl 39:2097–2099PubMedGoogle Scholar
  39. 39.
    Verdier L, Gharbi-Benarous J, Bertho G, Mauvais P, Girault JP (2002) Antibiotic resistance peptides: interaction of peptides conferring macrolide and ketolide resistance with Staphylococcus aureus ribosomes: conformation of bound peptides as determined by transferred NOE experiments. Biochemistry 41:4218–4229PubMedGoogle Scholar
  40. 40.
    Adams ER, Dratz EA, Gizachew D, Deleo FR, Yu L, Volpp BD, Vlases M, Jesaitis AJ, Quinn MT (1997) Interaction of human neutrophil flavocytochrome b with cytosolic proteins: transferred-NOESY NMR studies of a gp91phox C-terminal peptide bound to p47phox. Biochem J 325:249–257PubMedGoogle Scholar
  41. 41.
    Kleinberg ME, Mital D, Rotrosen D, Malech HL (1992) Characterization of a phagocyte cytochrome b558 91-kilodalton subunit functional domain: identification of peptide sequence and amino acids essential for activity. Biochemistry 31:2686–2690PubMedGoogle Scholar
  42. 42.
    Kleinjung J, Petit MC, Orlewski P, Mamalaki A, Tzartos SJ, Tsikaris V, Sakarellos-Daitsiotis M, Sakarellos C, Marraud M, Cung MT (2000) The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: a combined two-dimensional NMR, homology, and molecular modeling approach. Biopolymers 53:113–128PubMedGoogle Scholar
  43. 43.
    Inooka H, Ohtaki T, Kitahara O, Ikegami T, Endo S, Kitada C, Ogi K, Onda H, Fujino M, Shirakawa M (2001) Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol 8:161–165PubMedGoogle Scholar
  44. 44.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedGoogle Scholar
  45. 45.
    Shimaoka M, Springer TA (2003) Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov 2:703–716PubMedGoogle Scholar
  46. 46.
    Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA (2002) Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 296:151–155PubMedGoogle Scholar
  47. 47.
    Zwahlen C, Vincent SJF, Dibari L, Levitt MH, Bodenhausen G (1994) Quenching spin diffusion in selective measurements of transient overhauser effects in nuclear magnetic resonance applications to olignucleotides. J Am Chem Soc 116:362–368Google Scholar
  48. 48.
    Dechantsreiter MA, Planker E, Matha B et al (1999) N-Methylated cyclic RGD peptides as highly active and selective alpha(v)beta(3) integrin antagonists. Med Chem 42:3033–3040Google Scholar
  49. 49.
    Johnson MA, Rotondo A, Pinto BM (2002) NMR studies of the antibody-bound conformation of a carbohydrate-mimetic peptide. Biochemistry 41:2149–2157PubMedGoogle Scholar
  50. 50.
    Dalvit C, Pevarello P, Tatò M, Veronesi M, Vulpetti A, Sundström M (2000) J Biomol NMR 18(1):65–68 PMID:11061229PubMedGoogle Scholar
  51. 51.
    Chen A, Shapiro MJ (1998) NOE pumping: a novel NMR technique for identification of compounds with binding affinity to macromolecules. J Am Chem Soc 120:10258–10259Google Scholar
  52. 52.
    Dalvit C, Fogliatto G, Stewart A, Veronesi M, Stockman B (2001) WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J Biomol NMR 21:349–359PubMedGoogle Scholar
  53. 53.
    Dalvit C, Fasolini M, Flocco M, Knapp S, Pevarello P, Veronesi M (2002) NMR-Based screening with competition water-ligand observed via gradient spectroscopy experiments: detection of high-affinity ligands. J Med Chem 45:2610–2614PubMedGoogle Scholar
  54. 54.
    Mayer M, Meyer B (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew Chem Int Ed 38:1784–1788Google Scholar
  55. 55.
    Klein J, Meinecke R, Mayer M, Meyer B (1999) Detecting Binding Affinity to Immobilized Receptor Proteins in Compound Libraries by HR-MAS STD NMR. J Am Chem Soc 121:5336–5337Google Scholar
  56. 56.
    Tranqui L, Andrieux A, Hudry-Clergeon G, Ryckewaert JJ, Soyez S, Chapel A, Ginsberg MH, Plow EF, Marguerie G (1989) Differential structural requirements for fibrinogen binding to platelets and to endothelial cells. J Cell Biol 108:2519–2527PubMedGoogle Scholar
  57. 57.
    Meinecke R, Meyer B (2001) Determination of the binding specificity of an integral membrane protein by saturation transfer difference NMR: RGD peptide ligands binding to integrin alphaIIbbeta3. J Med Chem 44:3059–3065PubMedGoogle Scholar
  58. 58.
    Zhang L, Mattern RH, Malaney TI, Pierschbacher MD, Goodman M (2002) Receptor-bound conformation of an alpha(5)beta(1) integrin antagonist by 15N-edited 2D transferred nuclear overhauser effects. J Am Chem Soc 124:2862–2863PubMedGoogle Scholar
  59. 59.
    Fielding L, Fletcher D, Rutherford S, Kaur J, Mestres J (2003) Exploring the active site of human factor Xa protein by NMR screening of small molecule probes. Org Biomol Chem 1:4235–4241PubMedGoogle Scholar
  60. 60.
    Kooistra O, Herfurth L, Luneberg E, Frosch M, Peters T, Zahringer U (2002) Epitope mapping of the O-chain polysaccharide of Legionella pneumophila serogroup 1 lipopolysaccharide by saturation-transfer-difference NMR spectroscopy. Eur J Biochem 269:573–582PubMedGoogle Scholar
  61. 61.
    Wang YS, Liu D, Wyss DF (2004) Competition STD NMR for the detection of high-affinity ligands and NMR-based screening. Magn Reson Chem 42:485–489PubMedGoogle Scholar
  62. 62.
    Yan J, Kline AD, Mo H, Shapiro MJ, Zartler ER (2003) The effect of relaxation on the epitope mapping by saturation transfer difference NMR. J Magn Reson 163:270–276PubMedGoogle Scholar
  63. 63.
    Jayalakshmi V, Krishna NR (2002) Complete relaxation and conformational exchange matrix (CORCEMA) analysis of intermolecular saturation transfer effects in reversibly forming ligand-receptor complexes. J Magn Reson 155:106–118PubMedGoogle Scholar
  64. 64.
    Jayalakshmi V, Rama KN (2004) CORCEMA refinement of the bound ligand conformation within the protein binding pocket in reversibly forming weak complexes using STD-NMR intensities. J Magn Reson 168:36–45PubMedGoogle Scholar
  65. 65.
    Foster MP, Wuttke DS, Clemens KR, Jahnke W, Radhakrishnan I, Tennant L, Reymond M, Chung J, Wright PE (1998) Chemical shift as a probe of molecular interfaces: NMR studies of DNA binding by the three amino-terminal zinc finger domains from transcription factor IIIA. J Biomol NMR 12:51–71PubMedGoogle Scholar
  66. 66.
    Medek A, Hajduk PJ, Mack J, Fesik SW (2000) The use of differential chemical shifts for determining the binding site location and orientation of protein-bound ligands. J Am Chem Soc 122:1241–1242Google Scholar
  67. 67.
    Dornan J, Taylor P, Walkinshaw MD (2003) Structures of immunophilins and their ligand complexes. Curr Top Med Chem 3:1392–1409PubMedGoogle Scholar
  68. 68.
    Hajduk PJ, Burns DJ (2002) Integration of NMR and high-throughput screening. Comb Chem High Throughput Screen 5:613–621PubMedGoogle Scholar
  69. 69.
    Liu G, Xin Z, Pei Z, Hajduk PJ, Abad-Zapatero C, Hutchins CW, Zhao H, Lubben TH, Ballaron SJ, Haasch DL, Kaszubska W, Rondinone CM, Trevillyan JM, Jirousek MR (2003) Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J Med Chem 46:4232–4235PubMedGoogle Scholar
  70. 70.
    Puius YA, Zhao Y, Sullivan M, Lawrence DS, Almo SC, Zhang ZY (1997) Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. Proc Natl Acad Sci USA 94:13420–13425PubMedGoogle Scholar
  71. 71.
    Bolon PJ, Al Hashimi HM, Prestegard JH (1999) Residual dipolar coupling derived orientational constraints on ligand geometry in a 53 kDa protein-ligand complex. J Mol Biol 293:107–115PubMedGoogle Scholar
  72. 72.
    Lipsitz RS, Tjandra N (2004) Residual dipolar couplings in NMR structure analysis. Annu Rev Biophys Biomol Struct 33:387–413PubMedGoogle Scholar
  73. 73.
    Giesen AW, Homans SW, Brown JM (2003) Determination of protein global folds using backbone residual dipolar coupling and long-range NOE restraints. J Biomol NMR 25:63–71PubMedGoogle Scholar
  74. 74.
    Wedemeyer WJ, Rohl CA, Scherag HA (2002) Exact solutions for chemical bond orientations from residual dipolar couplings. J Biomol NMR 22:137–151PubMedGoogle Scholar
  75. 75.
    Wang L, Donald BR (2004) Exact solutions for internuclear vectors and backbone dihedral angles from NH residual dipolar couplings in two media, and their application in a systematic search algorithm for determining protein backbone structure. J Biomol NMR 29:223–242PubMedGoogle Scholar
  76. 76.
    Huang X, Moy F, Powers R (2000) Evaluation of the utility of NMR structures determined from minimal NOE-based restraints for structure-based drug design, using MMP-1 as an example. Biochemistry 39:13365–13375PubMedGoogle Scholar
  77. 77.
    Jain NU, Noble S, Prestegard JH (2003) Structural characterization of a mannose-binding protein-trimannoside complex using residual dipolar couplings. J Mol Biol 328:451–462PubMedGoogle Scholar
  78. 78.
    Tian F, Al Hashimi HM, Craighead JL, Prestegard JH (2001) Conformational analysis of a flexible oligosaccharide using residual dipolar couplings. J Am Chem Soc 123:485–492PubMedGoogle Scholar
  79. 79.
    Umemoto K, Leffler H, Venot A, Valafar H, Prestegard JH (2003) Conformational differences in liganded and unliganded states of Galectin-3. Biochemistry 42:3688–3695PubMedGoogle Scholar
  80. 80.
    Sillerud LO, Larson RS (2005) Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr Protein Pept Sci 6:151–169PubMedGoogle Scholar
  81. 81.
    Pellecchia M, Sebbel P, Hermanns U, Wuthrich K, Glockshuber R (1999) Pilus chaperone FimC-adhesin FimH interactions mapped by TROSY-NMR. Nat Struct Biol 6:336–339PubMedGoogle Scholar
  82. 82.
    Sun W, Yang J, Liu XQ (2004) Synthetic two-piece and three-piece split inteins for protein trans-splicing. J Biol Chem 279:35281–35286PubMedGoogle Scholar
  83. 83.
    David R, Richter MP, Beck-Sickinger AG (2004) Expressed protein ligation. Method and applications. Eur J Biochem 271:663–677PubMedGoogle Scholar
  84. 84.
    Fernandez C, Hilty C, Bonjour S, Adeishvili K, Pervushin K, Wuthrich K (2001) Solution NMR studies of the integral membrane proteins OmpX and OmpA from Escherichia coli. FEBS Lett 504:173–178PubMedGoogle Scholar
  85. 85.
    Fernandez C, Adeishvili K, Wuthrich K (2001) Transverse relaxation-optimized NMR spectroscopy with the outer membrane protein OmpX in dihexanoyl phosphatidylcholine micelles. Proc Natl Acad Sci USA 98:2358–2363PubMedGoogle Scholar
  86. 86.
    McElroy C, Manfredo A, Wendt A, Gollnick P, Foster M (2002) TROSY-NMR studies of the 91 kDa TRAP protein reveal allosteric control of a gene regulatory protein by ligand-altered flexibility. J Mol Biol 323:463–473PubMedGoogle Scholar
  87. 87.
    Wienk H, Maneg O, Lucke C, Pristovsek P, Lohr F, Ludwig B, Ruterjans H (2003) Interaction of cytochrome c with cytochrome c oxidase: an NMR study on two soluble fragments derived from Paracoccus denitrificans. Biochemistry 42:6005–6012PubMedGoogle Scholar
  88. 88.
    Yuan C, Li J, Mahajan A, Poi MJ, Byeon IJ, Tsai MD (2004) Solution structure of the human oncogenic protein gankyrin containing seven ankyrin repeats and analysis of its structure–function relationship. Biochemistry 43:12152–12161PubMedGoogle Scholar
  89. 89.
    Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M (2003) Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res 63:8118–8121PubMedGoogle Scholar
  90. 90.
    Morgan WD, Lock MJ, Frenkiel TA, Grainger M, Holder AA (2004) Malaria parasite-inhibitory antibody epitopes on Plasmodium falciparum merozoite surface protein-1(19) mapped by TROSY NMR. Mol Biochem Parasitol 138:29–36PubMedGoogle Scholar
  91. 91.
    Dalvit C, Fagerness PE, Hadden DTA, Sarver RW, Stockman BJ (2003) Fluorine-NMR experiments for high-throughput screening: theoretical aspects, practical considerations, and range of applicability. J Am Chem Soc 125:7696–7703PubMedGoogle Scholar
  92. 92.
    Dalvit C, Ardini E, Fogliatto GP, Mongelli N, Veronesi M (2004) Reliable high-throughput functional screening with 3-FABS. Drug Discov Today 9:595–602PubMedGoogle Scholar
  93. 93.
    Han CH, Sillerud LO (1986) Synthesis of [guanidino-13C]creatine and measurement of the creatine phosphokinase reaction in vitro by 13C NMR spectroscopy. Magn Reson Med 3:626–633PubMedGoogle Scholar
  94. 94.
    Bista M, Kowalska K, Janczyk W, Doemling A, Holak TA (2009) Robust NMR screening for lead compounds using tryptophan-containing proteins. J Am Chem Soc 131:7500–7501PubMedGoogle Scholar
  95. 95.
    D’Silva L, Ozdowy P, Krajewski M, Rothweiler U, Singh M, Holak TA (2005) Monitoring the effects of antagonists on protein-protein interactions with NMR spectroscopy. J Am Chem Soc 127:13220–13226PubMedGoogle Scholar
  96. 96.
    Rehm T, Huber R, Holak TA (2002) Application of NMR in structural proteomics: screening for proteins amenable to structural analysis. Structure 10:1613–1618PubMedGoogle Scholar
  97. 97.
    Swann SL, Song D, Sun C, Philip J, Hajduk PJ, Petros AM (2010) Labeled ligand displacement: extending NMR-based screening of protein targets. ACS Med Chem Lett 1:295–299Google Scholar
  98. 98.
    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 73:571–581PubMedGoogle Scholar
  99. 99.
    Zartler ER, Hanson J, Jones BE, Kline AD, Martin G, Mo H, Shapiro MJ, Wang R, Wu H, Yan J (2003) RAMPED-UP NMR: multiplexed NMR-based screening for drug discovery. J Am Chem Soc 125:10941–10946PubMedGoogle Scholar
  100. 100.
    Jahnke W, Ruedisser S, Zurini M (2001) Spin label enhanced NMR screening. J Am Chem Soc 123:3149–3150PubMedGoogle Scholar
  101. 101.
    Moy FJ, Lee A, Gavrin LK, Xu ZB, Sievers A, Kieras E, Stochaj W, Mosyak L, McKew J, Tsao DH (2010) Novel synthesis and structural characterization of a high-affinity paramagnetic kinase probe for the identification of non-ATP site binders by nuclear magnetic resonance. J Med Chem 53:1238–1249PubMedGoogle Scholar
  102. 102.
    John M, Pintacuda G, Park AY, Dixon NE, Otting G (2006) Structure determination of protein-ligand complexes by transferred paramagnetic shifts. J Am Chem Soc 128:12910–12916PubMedGoogle Scholar
  103. 103.
    Marquardsen T, Hofmann M, Hollander JG, Loch CM, Kiihne SR, Engelke F, Siegal G (2006) Development of a dual cell, flow-injection sample holder, and NMR probe for comparative ligand-binding studies. J Magn Reson 182:55–65PubMedGoogle Scholar
  104. 104.
    Kobayashi M, Retra K, Figaroa F, Hollander JG, Ab E, Heetebrij RJ, Irth H, Siegal G (2010) Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification. J Biomol Screen 15:978–989PubMedGoogle Scholar
  105. 105.
    Hajduk PJ, Meadows RP, Fesik SW (1999) NMR-based screening in drug discovery. Q Rev Biophys 32:211–240PubMedGoogle Scholar
  106. 106.
    Hajduk PJ, Gerfin T, Boehlen JM, Haberli M, Marek D, Fesik SW (1999) High-throughput nuclear magnetic resonance-based screening. J Med Chem 42:2315–2317PubMedGoogle Scholar
  107. 107.
    Tugarinov V, Sprangers R, Kay LE (2004) Line narrowing in methyl-TROSY using zero-quantum 1H-13C NMR spectroscopy. J Am Chem Soc 126:4921–4925PubMedGoogle Scholar
  108. 108.
    Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280:1–9PubMedGoogle Scholar
  109. 109.
    Rodriguez-Mias RA, Pellecchia M (2003) Use of selective Trp side chain labeling to characterize protein-protein and protein-ligand interactions by NMR spectroscopy. J Am Chem Soc 125:2892–2893PubMedGoogle Scholar
  110. 110.
    Dalvit C, Ardini E, Flocco M, Fogliatto GP, Mongelli N, Veronesi M (2003) A general NMR method for rapid, efficient, and reliable biochemical screening. J Am Chem Soc 125:14620–14625PubMedGoogle Scholar
  111. 111.
    Folkers GE, van Buuren BN, Kaptein R (2004) Expression screening, protein purification and NMR analysis of human protein domains for structural genomics. J Struct Funct Genomics 5:119–131PubMedGoogle Scholar
  112. 112.
    Scheich C, Leitner D, Sievert V, Leidert M, Schlegel B, Simon B, Letunic I, Bussow K, Diehl A (2004) Fast identification of folded human protein domains expressed in E. coli suitable for structural analysis. BMC Struct Biol 4:4PubMedGoogle Scholar
  113. 113.
    Kim S, Szyperski T (2003) GFT NMR, a new approach to rapidly obtain precise high-dimensional NMR spectral information. J Am Chem Soc 125:1385–1393PubMedGoogle Scholar
  114. 114.
    Xia Y, Zhu G, Veeraraghavan S, Gao X (2004) (3,2)D GFT-NMR experiments for fast data collection from proteins. J Biomol NMR 29:467–476PubMedGoogle Scholar
  115. 115.
    Orekhov VY, Ibraghimov I, Billeter M (2003) Optimizing resolution in multidimensional NMR by three-way decomposition. J Biomol NMR 27:165–173PubMedGoogle Scholar
  116. 116.
    Gutmanas A, Jarvoll P, Orekhov VY, Billeter M (2002) Three-way decomposition of a complete 3D 15N-NOESY-HSQC. J BiomolNMR 24:191–201Google Scholar
  117. 117.
    Korzhneva DM, Ibraghimov IV, Billeter M, Orekhov VY (2001) MUNIN: application of three-way decomposition to the analysis of heteronuclear NMR relaxation data. J Biomol NMR 21:263–268PubMedGoogle Scholar
  118. 118.
    Orekhov VY, Ibraghimov IV, Billeter M (2001) MUNIN: a new approach to multi-dimensional NMR spectra interpretation. J Biomol NMR 20:49–60PubMedGoogle Scholar
  119. 119.
    Damberg CS, Orekhov VY, Billeter M (2002) Automated analysis of large sets of heteronuclear correlation spectra in NMR-based drug discovery. J Med Chem 45:5649–5654PubMedGoogle Scholar
  120. 120.
    Deng Z, Chuaqui C, Singh J (2004) Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions. J Med Chem 47:337–344PubMedGoogle Scholar
  121. 121.
    Beger RD, Buzatu DA, Wilkes JG, Lay JO Jr (2001) (13)C NMR quantitative spectrometric data-activity relationship (QSDAR) models of steroids binding the aromatase enzyme. J Chem Inf Comput Sci 41:1360–1366PubMedGoogle Scholar
  122. 122.
    Beger RD, Freeman JP, Lay JO Jr, Wilkes JG, Miller DW (2001) Use of 13C NMR spectrometric data to produce a predictive model of estrogen receptor binding activity. J Chem Inf Comput Sci 41:219–224PubMedGoogle Scholar
  123. 123.
    Beger RD, Wilkes JG (2001) Developing 13C NMR quantitative spectrometric data-activity relationship (QSDAR) models of steroid binding to the corticosteroid binding globulin. J Comput Aided Mol Des 15:659–669PubMedGoogle Scholar
  124. 124.
    Beger RD, Buzatu DA, Wilkes JG (2002) Combining NMR spectral and structural data to form models of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls binding to the AhR. J Comput Aided Mol Des 16:727–740PubMedGoogle Scholar
  125. 125.
    Griffin JL (2004) Metabolic profiles to define the genome: can we hear the phenotypes? Philos Trans R Soc Lond B Biol Sci 359:857–871PubMedGoogle Scholar
  126. 126.
    Wishart DS (2008) Applications of metabolomics in drug discovery and development. Drugs R&D 9:307–322Google Scholar
  127. 127.
    Powers R (2009) NMR metabolomics and drug discovery. Magn Reson Chem 47:s2–s11PubMedGoogle Scholar
  128. 128.
    Homans SW (2004) NMR spectroscopy tools for structure-aided drug design. Angew Chem Int Ed Engl 43:290–300PubMedGoogle Scholar
  129. 129.
    Pellecchia M, Sem DS, Wuthrich K (2002) NMR in drug discovery. Nat Rev Drug Discov 1:211–219PubMedGoogle Scholar
  130. 130.
    Pellecchia M, Meininger D, Dong Q, Chang E, Jack R, Sem DS (2002) NMR-based structural characterization of large protein-ligand interactions. J Biomol NMR 22:165–173PubMedGoogle Scholar
  131. 131.
    Clore GM, Gronenborn AM (1994) Multidimensional heteronuclear muclear magnetic resonance of proteins. Methods Enzymol 239:349–363PubMedGoogle Scholar
  132. 132.
    Meadows RP, Nettesheim DG, Xu RX, Olejniczak ET, Petros AM, Holzman TF, Severin J, Gubbins E, Smith H, Fesik SW (1993) Three-dimensional structure of the FK506 binding protein/ascomycin complex in solution by heteronuclear three- and four-dimensional NMR. Biochemistry 32:754–765PubMedGoogle Scholar
  133. 133.
    Van Duyne GD, Standaert RF, Karplus PA, Schreiber SL, Clardy J (1991) Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. Science 252:839–842PubMedGoogle Scholar
  134. 134.
    Van Duyne GD, Standaert RF, Schreiber SL, Clardy J (1991) Atomic structure of the rapamycin human immunophilin FKBP-12 complex. J Am Chem Soc 113:7433–7434Google Scholar
  135. 135.
    Powers R (2009) Advances in nuclear magnetic resonance for drug discovery. Exp Opin Drug Discov 4:1077–1098Google Scholar
  136. 136.
    Pellecchia M, Bertini I, Cowburn D, Dalvit C, Giralt E, Jahnke W, James TL, Homans SW, Kessler H, Luchinat C, Meyer B, Oschkinat H, Peng J, Schwalbe H, Siegal G (2008) Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov 7:738–745PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyUNM HDC, University of New MexicoAlbuquerqueUSA
  2. 2.The University of New MexicoAlbuqerqueUSA

Personalised recommendations