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Targeting Protein–Protein Interactions and Fragment-Based Drug Discovery

  • Eugene Valkov
  • Tim Sharpe
  • May Marsh
  • Sandra Greive
  • Marko HyvönenEmail author
Chapter
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 317)

Abstract

Protein–protein interactions (PPI) are integral to the majority of biological functions. Targeting these interactions with small molecule inhibitors is of increased interest both in academia as well as in the pharmaceutical industry, both for therapeutic purposes and in the search for chemical tools for basic science. Although the number of well-characterised examples is still relatively modest, it is becoming apparent that many different kinds of interactions can be inhibited using drug-like small molecules. Compared to active site targeting, PPI inhibition suffers from the particular problem of more exposed and less defined binding sites, and this imposes significant experimental challenges to the development of PPI inhibitors. PPI interfaces are large, up to thousands of square angstroms, and there is still debate as to what part of the interface one should target. We will review recent developments in the field of PPI inhibition, with emphasis on fragment-based methods, and discuss various factors one should take into account when developing small molecule inhibitors targeted at PPI interfaces.

Keywords

Biophysical screening Fragment-based drug discovery Inhibitor Protein–protein interactions Structural biology 

Notes

Acknowledgments

This work was funded by The Wellcome Trust under Seeding Drug Discovery Initiative and the Strategic Award scheme.

References

  1. 1.
    Pammolli F, Magazzini L, Riccaboni M (2011) The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10(6):428–438Google Scholar
  2. 2.
    Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996Google Scholar
  3. 3.
    Schwikowski B, Uetz P, Fields S (2000) A network of protein-protein interactions in yeast. Nat Biotechnol 18(12):1257–1261Google Scholar
  4. 4.
    Schachter V (2002) Bioinformatics of large-scale protein interaction networks. Biotechniques 32 (3 suppl):S16–S27Google Scholar
  5. 5.
    Schachter V (2002) Protein-interaction networks: from experiments to analysis. Drug Discov Today 7(11):S48–S54Google Scholar
  6. 6.
    Grigoriev A (2003) On the number of protein-protein interactions in the yeast proteome. Nucleic Acids Res 31(14):4157–4161Google Scholar
  7. 7.
    Kumar A et al (2002) Subcellular localization of the yeast proteome. Genes Dev 16(6):707–719Google Scholar
  8. 8.
    Ramani AK et al (2005) Consolidating the set of known human protein-protein interactions in preparation for large-scale mapping of the human interactome. Genome Biol 6(5):R40Google Scholar
  9. 9.
    Voisey J, Morris CP (2008) SNP technologies for drug discovery: a current review. Curr Drug Discov Technol 5(3):230–235Google Scholar
  10. 10.
    Fabian MA et al (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23(3):329–336Google Scholar
  11. 11.
    Hughes B (2011) Large drugs outdo small. Nat Biotechnol 29(4):296Google Scholar
  12. 12.
    Carlson SM, White FM (2011) Using small molecules and chemical genetics to interrogate signaling networks. ACS Chem Biol 6(1):75–85Google Scholar
  13. 13.
    Bossi A, Lehner B (2009) Tissue specificity and the human protein interaction network. Mol Syst Biol 5:260Google Scholar
  14. 14.
    Lehne B, Schlitt T (2009) Protein-protein interaction databases: keeping up with growing interactomes. Hum Genomics 3(3):291–297Google Scholar
  15. 15.
    Shoemaker BA, Panchenko AR (2007) Deciphering protein-protein interactions. Part I. Experimental techniques and databases. PLoS Comput Biol 3(3):e42Google Scholar
  16. 16.
    Shoemaker BA, Panchenko AR (2007) Deciphering protein-protein interactions. Part II. Computational methods to predict protein and domain interaction partners. PLoS Comput Biol 3(4):e43Google Scholar
  17. 17.
    Cusick ME et al (2009) Literature-curated protein interaction datasets. Nat Methods 6(1):39–46Google Scholar
  18. 18.
    Salwinski L et al (2009) Recurated protein interaction datasets. Nat Methods 6(12):860–861Google Scholar
  19. 19.
    Szklarczyk D et al (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39(Database issue): D561–D568Google Scholar
  20. 20.
    Aranda B et al (2010) The IntAct molecular interaction database in 2010. Nucleic Acids Res 38(suppl 1): D525–D531Google Scholar
  21. 21.
    Ceol A et al (2010) MINT, the molecular interaction database: 2009 update. Nucleic Acids Res 38(suppl 1):D532–D539Google Scholar
  22. 22.
    Hernandez-Toro J, Prieto C, De las Rivas J (2007) APID2NET: unified interactome graphic analyzer. Bioinformatics 23(18):2495–2497Google Scholar
  23. 23.
    Prieto C et al (2008) Human gene coexpression landscape: confident network derived from tissue transcriptomic profiles. PLoS One 3(12):e3911Google Scholar
  24. 24.
    Wu J et al (2009) Integrated network analysis platform for protein-protein interactions. Nat Methods 6(1):75–77Google Scholar
  25. 25.
    Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285(5):2177–2198Google Scholar
  26. 26.
    Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci USA 93(1):13–20Google Scholar
  27. 27.
    Stites WE (1997) Protein-protein interactions: interface structure, binding thermodynamics, and mutational analysis. Chem Rev 97(5):1233–1250Google Scholar
  28. 28.
    Ivanov YD, Kanaeva IP, Archakov AI (2000) Optical biosensor study of ternary complex formation in a cytochrome P4502B4 system. Biochem Biophys Res Commun 273(2):750–752Google Scholar
  29. 29.
    Ivanov YD et al (1999) The optical biosensor studies on the role of hydrophobic tails of NADPH-cytochrome P450 reductase and cytochromes P450 2B4 and b5 upon productive complex formation within a monomeric reconstituted system. Arch Biochem Biophys 362(1):87–93Google Scholar
  30. 30.
    Lijnzaad P, Argos P (1997) Hydrophobic patches on protein subunit interfaces: characteristics and prediction. Proteins 28(3):333–343Google Scholar
  31. 31.
    Tsai CJ et al (1997) Studies of protein-protein interfaces: a statistical analysis of the hydrophobic effect. Protein Sci 6(1):53–64Google Scholar
  32. 32.
    Dall'Acqua W et al (1998) A mutational analysis of binding interactions in an antigen-antibody protein-protein complex. Biochemistry 37(22):7981–7991Google Scholar
  33. 33.
    Vaughan CK, Buckle AM, Fersht AR (1999) Structural response to mutation at a protein-protein interface. J Mol Biol 286(5):1487–1506Google Scholar
  34. 34.
    Janin J (1999) Wet and dry interfaces: the role of solvent in protein-protein and protein-DNA recognition. Structure 7(12):R277–R279Google Scholar
  35. 35.
    Larsen TA, Olson AJ, Goodsell DS (1998) Morphology of protein-protein interfaces. Structure 6(4):421–427Google Scholar
  36. 36.
    Xu D, Lin SL, Nussinov R (1997) Protein binding versus protein folding: the role of hydrophilic bridges in protein associations. J Mol Biol 265(1):68–84Google Scholar
  37. 37.
    Perkins JR et al (2010) Transient protein-protein interactions: structural, functional, and network properties. Structure 18(10):1233–1243Google Scholar
  38. 38.
    Fersht A (1999) Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding. W.H. Freeman, New York, xxi, p 631Google Scholar
  39. 39.
    Xu D, Tsai CJ, Nussinov R (1997) Hydrogen bonds and salt bridges across protein-protein interfaces. Protein Eng 10(9):999–1012Google Scholar
  40. 40.
    Ivanov AS et al (2007) Protein-protein interactions as new targets for drug design: virtual and experimental approaches. J Bioinform Comput Biol 5(2B):579–592Google Scholar
  41. 41.
    Sheinerman FB, Norel R, Honig B (2000) Electrostatic aspects of protein-protein interactions. Curr Opin Struct Biol 10(2):153–159Google Scholar
  42. 42.
    Stevens JM, Armstrong RN, Dirr HW (2000) Electrostatic interactions affecting the active site of class sigma glutathione S-transferase. Biochem J 347(Pt 1):193–197Google Scholar
  43. 43.
    Vijayakumar M et al (1998) Electrostatic enhancement of diffusion-controlled protein-protein association: comparison of theory and experiment on barnase and barstar. J Mol Biol 278(5):1015–1024Google Scholar
  44. 44.
    McCoy AJ, Chandana Epa V, Colman PM (1997) Electrostatic complementarity at protein/protein interfaces. J Mol Biol 268(2):570–584Google Scholar
  45. 45.
    Camacho CJ et al (1999) Free energy landscapes of encounter complexes in protein-protein association. Biophys J 76(3):1166–1178Google Scholar
  46. 46.
    Neira JL, Vazquez E, Fersht AR (2000) Stability and folding of the protein complexes of barnase. Eur J Biochem 267(10):2859–2870Google Scholar
  47. 47.
    Buckle AM, Schreiber G, Fersht AR (1994) Protein-protein recognition: crystal structural analysis of a barnase-barstar complex at 2.0-A resolution. Biochemistry 33(30):8878–8889Google Scholar
  48. 48.
    Serrano L, Day AG, Fersht AR (1993) Step-wise mutation of barnase to binase. A procedure for engineering increased stability of proteins and an experimental analysis of the evolution of protein stability. J Mol Biol 233(2):305–312Google Scholar
  49. 49.
    Schreiber G, Fersht AR (1993) Interaction of barnase with its polypeptide inhibitor barstar studied by protein engineering. Biochemistry 32(19):5145–5150Google Scholar
  50. 50.
    Wells JA (1996) Binding in the growth hormone receptor complex. Proc Natl Acad Sci USA 93(1):1–6Google Scholar
  51. 51.
    Tsai CJ et al (1996) Protein-protein interfaces: architectures and interactions in protein-protein interfaces and in protein cores. Their similarities and differences. Crit Rev Biochem Mol Biol 31(2):127–152Google Scholar
  52. 52.
    Kauzmann W (1959) Some factors in the interpretation of protein denaturation. Adv Protein Chem 14:1–63Google Scholar
  53. 53.
    Tanford C (1980) The hydrophobic effect: formation of micelles and biological membranes, 2nd edn. Wiley, New York, ix, p 233Google Scholar
  54. 54.
    Olsson TS et al (2008) The thermodynamics of protein-ligand interaction and solvation: insights for ligand design. J Mol Biol 384(4):1002–1017Google Scholar
  55. 55.
    Betts MJ, Sternberg MJ (1999) An analysis of conformational changes on protein-protein association: implications for predictive docking. Protein Eng 12(4):271–283Google Scholar
  56. 56.
    Li W et al (2004) Highly discriminating protein-protein interaction specificities in the context of a conserved binding energy hotspot. J Mol Biol 337(3):743–759Google Scholar
  57. 57.
    Schreiber G, Haran G, Zhou HX (2009) Fundamental aspects of protein-protein association kinetics. Chem Rev 109(3):839–860Google Scholar
  58. 58.
    Finkelstein AV, Janin J (1989) The price of lost freedom: entropy of bimolecular complex formation. Protein Eng 3(1):1–3Google Scholar
  59. 59.
    Chothia C (1974) Hydrophobic bonding and accessible surface area in proteins. Nature 248(446):338–339Google Scholar
  60. 60.
    Schellman JA (1997) Temperature, stability, and the hydrophobic interaction. Biophys J 73(6):2960–2964Google Scholar
  61. 61.
    Baldwin RL (1996) How Hofmeister ion interactions affect protein stability. Biophys J 71(4):2056–2063Google Scholar
  62. 62.
    Jackson SE, Fersht AR (1993) Contribution of long-range electrostatic interactions to the stabilization of the catalytic transition state of the serine protease subtilisin BPN'. Biochemistry 32(50):13909–13916Google Scholar
  63. 63.
    Lorch M et al (1999) Effects of core mutations on the folding of a beta-sheet protein: implications for backbone organization in the I-state. Biochemistry 38(4):1377–1385Google Scholar
  64. 64.
    Fersht AR et al (1985) Hydrogen bonding and biological specificity analysed by protein engineering. Nature 314(6008):235–238Google Scholar
  65. 65.
    Strop P, Mayo SL (2000) Contribution of surface salt bridges to protein stability. Biochemistry 39(6):1251–1255Google Scholar
  66. 66.
    Luisi DL et al (2003) Surface salt bridges, double-mutant cycles, and protein stability: an experimental and computational analysis of the interaction of the Asp 23 side chain with the N-terminus of the N-terminal domain of the ribosomal protein l9. Biochemistry 42(23):7050–7060Google Scholar
  67. 67.
    Daopin S et al (1991) Structural and thermodynamic analysis of the packing of two alpha-helices in bacteriophage T4 lysozyme. J Mol Biol 221(2):647–667Google Scholar
  68. 68.
    Sali D, Bycroft M, Fersht AR (1991) Surface electrostatic interactions contribute little of stability of barnase. J Mol Biol 220(3):779–788Google Scholar
  69. 69.
    Prajapati RS et al (2006) Contribution of cation-pi interactions to protein stability. Biochemistry 45(50):15000–15010Google Scholar
  70. 70.
    Murray CW, Verdonk ML (2002) The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J Comput Aided Mol Des 16(10):741–753Google Scholar
  71. 71.
    Chang CE, Gilson MK (2004) Free energy, entropy, and induced fit in host-guest recognition: calculations with the second-generation mining minima algorithm. J Am Chem Soc 126(40):13156–13164Google Scholar
  72. 72.
    Chang CE, Chen W, Gilson MK (2007) Ligand configurational entropy and protein binding. Proc Natl Acad Sci USA 104(5):1534–1539Google Scholar
  73. 73.
    Cunningham BC, Wells JA (1997) Minimized proteins. Curr Opin Struct Biol 7(4):457–462Google Scholar
  74. 74.
    Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267(5196):383–386Google Scholar
  75. 75.
    DeLano WL (2002) Unraveling hot spots in binding interfaces: progress and challenges. Curr Opin Struct Biol 12(1):14–20Google Scholar
  76. 76.
    Bass SH, Mulkerrin MG, Wells JA (1991) A systematic mutational analysis of hormone-binding determinants in the human growth hormone receptor. Proc Natl Acad Sci USA 88(10):4498–4502Google Scholar
  77. 77.
    Thorn KS, Bogan AA (2001) ASEdb: a database of alanine mutations and their effects on the free energy of binding in protein interactions. Bioinformatics 17(3):284–285Google Scholar
  78. 78.
    Moreira IS, Fernandes PA, Ramos MJ (2007) Hot spots–a review of the protein-protein interface determinant amino-acid residues. Proteins 68(4):803–812Google Scholar
  79. 79.
    Keskin O, Ma B, Nussinov R (2005) Hot regions in protein–protein interactions: the organization and contribution of structurally conserved hot spot residues. J Mol Biol 345(5):1281–1294Google Scholar
  80. 80.
    Li X et al (2004) Protein-protein interactions: hot spots and structurally conserved residues often locate in complemented pockets that pre-organized in the unbound states: implications for docking. J Mol Biol 344(3):781–795Google Scholar
  81. 81.
    Jin L, Wells JA (1994) Dissecting the energetics of an antibody-antigen interface by alanine shaving and molecular grafting. Protein Sci 3(12):2351–2357Google Scholar
  82. 82.
    Braisted AC et al (2003) Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J Am Chem Soc 125(13):3714–3715Google Scholar
  83. 83.
    Thanos CD, DeLano WL, Wells JA (2006) Hot-spot mimicry of a cytokine receptor by a small molecule. Proc Natl Acad Sci USA 103(42):15422–15427Google Scholar
  84. 84.
    Hajduk PJ, Huth JR, Fesik SW (2005) Druggability indices for protein targets derived from NMR-based screening data. J Med Chem 48(7):2518–2525Google Scholar
  85. 85.
    Hajduk PJ, Huth JR, Tse C (2005) Predicting protein druggability. Drug Discov Today 10(23–24):1675–1682Google Scholar
  86. 86.
    Sia SK et al (2002) Short constrained peptides that inhibit HIV-1 entry. Proc Natl Acad Sci USA 99(23):14664–14669Google Scholar
  87. 87.
    Walensky LD et al (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305(5689):1466–1470Google Scholar
  88. 88.
    Wang D, Liao W, Arora PS (2005) Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL. Angew Chem Int Ed Engl 44(40):6525–6529Google Scholar
  89. 89.
    Kaul R, Deechongkit S, Kelly JW (2002) Synthesis of a negatively charged dibenzofuran-based beta-turn mimetic and its incorporation into the WW miniprotein-enhanced solubility without a loss of thermodynamic stability. J Am Chem Soc 124(40):11900–11907Google Scholar
  90. 90.
    Arnold U et al (2002) Protein prosthesis: a semisynthetic enzyme with a beta-peptide reverse turn. J Am Chem Soc 124(29):8522–8523Google Scholar
  91. 91.
    Fasan R et al (2006) Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction. Chembiochem 7(3):515–526Google Scholar
  92. 92.
    Harker EA et al (2009) Beta-peptides with improved affinity for hDM2 and hDMX. Bioorg Med Chem 17(5):2038–2046Google Scholar
  93. 93.
    Stephens OM et al (2005) Inhibiting HIV fusion with a beta-peptide foldamer. J Am Chem Soc 127(38):13126–13127Google Scholar
  94. 94.
    Sadowsky JD et al (2007) (alpha/beta + alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. J Am Chem Soc 129(1):139–154Google Scholar
  95. 95.
    Smith AB 3rd et al (1997) An orally bioavailable pyrrolinone inhibitor of HIV-1 protease: computational analysis and X-ray crystal structure of the enzyme complex. J Med Chem 40(16):2440–2444Google Scholar
  96. 96.
    Blaskovich MA et al (2000) Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. Nat Biotechnol 18(10):1065–1070Google Scholar
  97. 97.
    Orner BP, Ernst JT, Hamilton AD (2001) Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. J Am Chem Soc 123(22):5382–5383Google Scholar
  98. 98.
    Saraogi I, Hamilton AD (2008) alpha-Helix mimetics as inhibitors of protein-protein interactions. Biochem Soc Trans 36(Pt 6):1414–1417Google Scholar
  99. 99.
    Rodriguez JM et al (2009) Synthetic inhibitors of extended helix-protein interactions based on a biphenyl 4,4'-dicarboxamide scaffold. Chembiochem 10(5):829–833Google Scholar
  100. 100.
    Leung DK, Yang Z, Breslow R (2000) Selective disruption of protein aggregation by cyclodextrin dimers. Proc Natl Acad Sci USA 97(10):5050–5053Google Scholar
  101. 101.
    Ojida A et al (2003) Cross-linking strategy for molecular recognition and fluorescent sensing of a multi-phosphorylated peptide in aqueous solution. J Am Chem Soc 125(34):10184–10185Google Scholar
  102. 102.
    Hayashida O, Ogawa N, Uchiyama M (2007) Surface recognition and fluorescence sensing of histone by dansyl-appended cyclophane-based resorcinarene trimer. J Am Chem Soc 129(44):13698–13705Google Scholar
  103. 103.
    McMillan K et al (2000) Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc Natl Acad Sci USA 97(4):1506–1511Google Scholar
  104. 104.
    Berg T (2008) Small-molecule inhibitors of protein-protein interactions. Curr Opin Drug Discov Devel 11(5):666–674Google Scholar
  105. 105.
    Fischer U, Schulze-Osthoff K (2005) Apoptosis-based therapies and drug targets. Cell Death Differ 12(Suppl 1):942–961Google Scholar
  106. 106.
    Fry DC (2008) Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr Protein Pept Sci 9(3):240–247Google Scholar
  107. 107.
    Gonzalez-Ruiz D, Gohlke H (2006) Targeting protein-protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. Curr Med Chem 13(22):2607–2625Google Scholar
  108. 108.
    Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172):1001–1009Google Scholar
  109. 109.
    Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2(3):112–118Google Scholar
  110. 110.
    Blundell TL et al (2006) Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philos Trans R Soc Lond B Biol Sci 361(1467):413–423Google Scholar
  111. 111.
    Higueruelo AP et al (2009) Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database. Chem Biol Drug Des 74(5):457–467Google Scholar
  112. 112.
    Boelsterli UA et al (2006) Bioactivation and hepatotoxicity of nitroaromatic drugs. Curr Drug Metab 7(7):715–727Google Scholar
  113. 113.
    Hopkins AL, Groom CR, Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9(10):430–431Google Scholar
  114. 114.
    Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1(3):198–210Google Scholar
  115. 115.
    Mossessova E, Corpina RA, Goldberg J (2003) Crystal structure of ARF1*Sec7 complexed with Brefeldin A and its implications for the guanine nucleotide exchange mechanism. Mol Cell 12(6):1403–1411Google Scholar
  116. 116.
    Viaud J et al (2007) Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein-protein complexes. Proc Natl Acad Sci USA 104(25):10370–10375Google Scholar
  117. 117.
    Pellicena P, Kuriyan J (2006) Protein-protein interactions in the allosteric regulation of protein kinases. Curr Opin Struct Biol 16(6):702–709Google Scholar
  118. 118.
    Jahnke W et al (2010) Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat Chem Biol 6(9):660–666Google Scholar
  119. 119.
    Kiessling A et al (2006) Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. Chem Biol 13(7):745–751Google Scholar
  120. 120.
    Lepourcelet M et al (2004) Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 5(1):91–102Google Scholar
  121. 121.
    Trosset JY et al (2006) Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 64(1):60–67Google Scholar
  122. 122.
    Vassilev LT et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848Google Scholar
  123. 123.
    Buchwald P (2010) Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life 62(10):724–731Google Scholar
  124. 124.
    Congreve M, Murray CW, Blundell TL (2005) Structural biology and drug discovery. Drug Discov Today 10(13):895–907Google Scholar
  125. 125.
    Coyne AG, Scott DE, Abell C (2010) Drugging challenging targets using fragment-based approaches. Curr Opin Chem Biol 14(3):299–307Google Scholar
  126. 126.
    Rees DC et al (2004) Fragment-based lead discovery. Nat Rev Drug Discov 3(8):660–672Google Scholar
  127. 127.
    Lugovskoy AA et al (2002) A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors. J Am Chem Soc 124(7):1234–1240Google Scholar
  128. 128.
    Raimundo BC et al (2004) Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein-protein interactions. J Med Chem 47(12):3111–3130Google Scholar
  129. 129.
    Tilley JW et al (1997) Identification of a Small Molecule Inhibitor of the IL-2/IL-2Rα Receptor Interaction Which Binds to IL-2. J Am Chem Soc 119(32):7589–7590Google Scholar
  130. 130.
    Tsao DH et al (2006) Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. Bioorg Med Chem 14(23):7953–7961Google Scholar
  131. 131.
    Erlanson DA et al (2003) In situ assembly of enzyme inhibitors using extended tethering. Nat Biotechnol 21(3):308–314Google Scholar
  132. 132.
    Hajduk PJ et al (1997) Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 119(25):5818–5827Google Scholar
  133. 133.
    Howard N et al (2006) Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. J Med Chem 49(4):1346–1355Google Scholar
  134. 134.
    Nordstrom H et al (2008) Identification of MMP-12 inhibitors by using biosensor-based screening of a fragment library. J Med Chem 51(12):3449–3459Google Scholar
  135. 135.
    Hamalainen MD et al (2008) Label-free primary screening and affinity ranking of fragment libraries using parallel analysis of protein panels. J Biomol Screen 13(3):202–209Google Scholar
  136. 136.
    Mikuni J et al (2010) A fluorescence correlation spectroscopy-based assay for fragment screening of slowly inhibiting protein-peptide interaction inhibitors. Anal Biochem 402(1):26–31Google Scholar
  137. 137.
    Sullivan JE et al (2005) Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase. Biochemistry 44(50):16475–16490Google Scholar
  138. 138.
    Haines DS et al (1994) Physical and functional interaction between wild-type p53 and mdm2 proteins. Mol Cell Biol 14(2):1171–1178Google Scholar
  139. 139.
    Sattler M et al (1997) Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275(5302):983–986Google Scholar
  140. 140.
    Voss SD et al (1993) Identification of a direct interaction between interleukin 2 and the p64 interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 90(6):2428–2432Google Scholar
  141. 141.
    Knight SM et al (2002) A fluorescence polarization assay for the identification of inhibitors of the p53-DM2 protein-protein interaction. Anal Biochem 300(2):230–236Google Scholar
  142. 142.
    Wan KF et al (2009) Differential scanning fluorimetry as secondary screening platform for small molecule inhibitors of Bcl-XL. Cell Cycle 8(23):3943–3952Google Scholar
  143. 143.
    Rothe A, Hosse RJ, Power BE (2006) In vitro display technologies reveal novel biopharmaceutics. FASEB J 20(10):1599–1610Google Scholar
  144. 144.
    Bottger A et al (1997) Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr Biol 7(11):860–869Google Scholar
  145. 145.
    Ladbury JE et al (1995) Measurement of the binding of tyrosyl phosphopeptides to SH2 domains: a reappraisal. Proc Natl Acad Sci USA 92(8):3199–3203Google Scholar
  146. 146.
    Hajduk PJ, Meadows RP, Fesik SW (1999) NMR-based screening in drug discovery. Q Rev Biophys 32:211–240Google Scholar
  147. 147.
    Meyer B, Peters T (2003) NMR spectroscopy of proteins NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew Chem Int Ed Engl 42:864–890Google Scholar
  148. 148.
    Shuker SB et al (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274(5292):1531–1534Google Scholar
  149. 149.
    D'Silva L et al (2005) Monitoring the effects of antagonists on protein-protein interactions with NMR spectroscopy. J Am Chem Soc 127(38):13220–13226Google Scholar
  150. 150.
    Emerson SD et al (2003) NMR characterization of interleukin-2 in complexes with the IL-2Ralpha receptor component, and with low molecular weight compounds that inhibit the IL-2/IL-Ralpha interaction. Protein Sci 12(4):811–822Google Scholar
  151. 151.
    Dalvit C et al (2001) WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J Biomol NMR 21(4):349–359Google Scholar
  152. 152.
    Major LL, Smith TK (2011) Screening the MayBridge Rule of 3 Fragment Library for Compounds That Interact with the Trypanosoma brucei myo-Inositol-3-Phosphate Synthase and/or Show Trypanocidal Activity. Molecular Biology International 2011:1–14Google Scholar
  153. 153.
    Niesen FH, Berglund H, Vedadi M (2007) The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc 2(9):2212–2221Google Scholar
  154. 154.
    Koblish HK et al (2006) Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5(1):160–169Google Scholar
  155. 155.
    Karlsson R, Falt A (1997) Experimental design for kinetic analysis of protein-protein interactions with surface plasmon resonance biosensors. J Immunol Methods 200(1–2):121–133Google Scholar
  156. 156.
    de Kloe GE et al (2010) Surface plasmon resonance biosensor based fragment screening using acetylcholine binding protein identifies ligand efficiency hot spots (LE hot spots) by deconstruction of nicotinic acetylcholine receptor alpha7 ligands. J Med Chem 53(19):7192–7201Google Scholar
  157. 157.
    Perspicace S et al (2009) Fragment-based screening using surface plasmon resonance technology. J Biomol Screen 14(4):337–349Google Scholar
  158. 158.
    Arkin MR et al (2003) Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci USA 100(4):1603–1608Google Scholar
  159. 159.
    Day YS et al (2002) Direct comparison of binding equilibrium, thermodynamic, and rate constants determined by surface- and solution-based biophysical methods. Protein Sci 11(5):1017–1025Google Scholar
  160. 160.
    Edink E et al (2011) Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. J Am Chem Soc 133(14):5363–5371Google Scholar
  161. 161.
    Giannetti AM, Koch BD, Browner MF (2008) Surface plasmon resonance based assay for the detection and characterization of promiscuous inhibitors. J Med Chem 51(3):574–580Google Scholar
  162. 162.
    White PW et al (2003) Inhibition of human papillomavirus DNA replication by small molecule antagonists of the E1-E2 protein interaction. J Biol Chem 278(29):26765–26772Google Scholar
  163. 163.
    Torres FE et al (2010) Higher throughput calorimetry: opportunities, approaches and challenges. Curr Opin Struct Biol 20(5):598–605Google Scholar
  164. 164.
    Lakowicz JR (2006) Principles of fluorescence spectroscopy, 3rd edn. Springer, New York, xxvi, p 954Google Scholar
  165. 165.
    Degterev A et al (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3(2):173–182Google Scholar
  166. 166.
    Ding K et al (2005) Structure-based design of potent non-peptide MDM2 inhibitors. J Am Chem Soc 127(29):10130–10131Google Scholar
  167. 167.
    Ding K et al (2006) Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 49(12):3432–3435Google Scholar
  168. 168.
    Petros AM et al (2006) Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem 49(2):656–663Google Scholar
  169. 169.
    Titolo S et al (2003) Characterization of the minimal DNA binding domain of the human papillomavirus e1 helicase: fluorescence anisotropy studies and characterization of a dimerization-defective mutant protein. J Virol 77(9):5178–5191Google Scholar
  170. 170.
    Dams G et al (2007) A time-resolved fluorescence assay to identify small-molecule inhibitors of HIV-1 fusion. J Biomol Screen 12(6):865–874Google Scholar
  171. 171.
    Stallings-Mann M et al (2006) A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. Cancer Res 66(3):1767–1774Google Scholar
  172. 172.
    Bergendahl V, Heyduk T, Burgess RR (2003) Luminescence resonance energy transfer-based high-throughput screening assay for inhibitors of essential protein-protein interactions in bacterial RNA polymerase. Appl Environ Microbiol 69(3):1492–1498Google Scholar
  173. 173.
    Erlanson DA, Wells JA, Braisted AC (2004) Tethering: fragment-based drug discovery. Annu Rev Biophys Biomol Struct 33:199–223Google Scholar
  174. 174.
    Choong IC et al (2002) Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design. J Med Chem 45(23):5005–5022Google Scholar
  175. 175.
    Blundell TL, Jhoti H, Abell C (2002) High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 1(1):45–54Google Scholar
  176. 176.
    Verlinde CLMJ et al (1977) Anti-trypanosomiasis drug development based on structures of glycolytic enzymes. In: Veerapandian P (ed) Structure-based drug design. Marcel Dekker, New York, pp 365–394Google Scholar
  177. 177.
    Hubbard RE et al (2007) The SeeDs approach: integrating fragments into drug discovery. Curr Top Med Chem 7(16):1568–1581Google Scholar
  178. 178.
    Hartshorn MJ et al (2005) Fragment-based lead discovery using X-ray crystallography. J Med Chem 48(2):403–413Google Scholar
  179. 179.
    Nienaber VL et al (2000) Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol 18(10):1105–1108Google Scholar
  180. 180.
    Davies TG et al (2006) Pyramid: an integrated platform for fragment-based drug discovery. In: Fragment-based approaches in drug discovery. Wiley-VCH Verlag GmbH & Co. KGaA. p 193–214Google Scholar
  181. 181.
    Spurlino JC (2011) Fragment screening purely with protein crystallography. Methods Enzymol 493:321–356Google Scholar
  182. 182.
    Carr R, Jhoti H (2002) Structure-based screening of low-affinity compounds. Drug Discov Today 7(9):522–527Google Scholar
  183. 183.
    Murray CW, Blundell TL (2010) Structural biology in fragment-based drug design. Curr Opin Struct Biol 20(4):497–507Google Scholar
  184. 184.
    Hassell AM et al (2007) Crystallization of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 63(Pt 1):72–79Google Scholar
  185. 185.
    Skarzynski T, Thorpe J (2006) Industrial perspective on X-ray data collection and analysis. Acta Crystallogr D Biol Crystallogr 62(Pt 1):102–107Google Scholar
  186. 186.
    D'Arcy A, Villard F, Marsh M (2007) An automated microseed matrix-screening method for protein crystallization. Acta Crystallogr D Biol Crystallogr 63(Pt 4):550–554Google Scholar
  187. 187.
    Carugo O, Argos P (1997) Protein-protein crystal-packing contacts. Protein Sci 6(10): 2261–2263Google Scholar
  188. 188.
    Janin J, Rodier F (1995) Protein-protein interaction at crystal contacts. Proteins 23(4):580–587Google Scholar
  189. 189.
    Sledz P et al (2011) From crystal packing to molecular recognition: prediction and discovery of a binding site on the surface of polo-like kinase 1. Angew Chem Int Ed Engl 50(17):4003–4006Google Scholar
  190. 190.
    Zhang X et al (2006) An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125(6):1137–1149Google Scholar
  191. 191.
    Janin J (1997) Specific versus non-specific contacts in protein crystals. Nat Struct Biol 4(12):973–974Google Scholar
  192. 192.
    Janin J et al (2007) Macromolecular recognition in the Protein Data Bank. Acta Crystallogr D Biol Crystallogr 63(Pt 1):1–8Google Scholar
  193. 193.
    Gandhi L et al (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29(7):909–916Google Scholar
  194. 194.
    Erlanson DA (2011) Introduction to fragment-based drug discovery. Top Curr Chem DOI: 10.1007/128_2011_180
  195. 195.
    Wyss DF, Wang Y-S, Eaton HL, Strickland C, Voigt JH, Zhu Z, Stamford AW (2011) Combining NMR and X-ray crystallography in fragment-based drug discovery: Discovery of highly potent and selective BACE-1 inhibitors. Top Curr Chem DOI: 10.1007/128_2011_183
  196. 196.
    Davies TG, Tickle IJ (2011) Fragment screening using X-ray crystallography. Top Curr Chem DOI: 10.1007/128_2011_179
  197. 197.
    Hennig M, Ruf A, Huber W (2011) Combining biophysical screening and X-ray crystallography for fragment-based drug discovery. Top Curr Chem DOI: 10.1007/128_2011_225

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Eugene Valkov
    • 1
  • Tim Sharpe
    • 1
  • May Marsh
    • 1
  • Sandra Greive
    • 1
  • Marko Hyvönen
    • 1
    Email author
  1. 1.Department of BiochemistryUniversity of CambridgeCambridgeUK

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