Fragment Screening and HIV Therapeutics

  • Joseph D. Bauman
  • Disha Patel
  • Eddy Arnold
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 317)


Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target.


Drug design Fragment screening HIV Protease Reverse transcriptase Surface plasmon resonance X-ray crystallography 



Acquired immune deficiency syndrome


Calculated logarithm of octanol–water partition coefficient


Highly active antiretroviral therapy


Human immunodeficiency virus


Concentration of a compound leading to 50% enzyme inhibition




Isothermal calorimetry


Dissociation constant


Ligand efficiency


Mass spectroscopy


Nuclear magnetic resonance


Non-nucleoside reverse transcriptase inhibitor


Nucleoside/nucleotide reverse transcriptase inhibitor




Reverse transcriptase


Surface plasmon resonance


  1. 1.
    World Health Organization (2008) World Health Statistics
  2. 2.
    Mehellou Y, De Clercq E (2010) J Med Chem 53:521Google Scholar
  3. 3.
    Hadjuk PJ, Greer J (2007) Nat Rev Drug Discov 6:211–219CrossRefGoogle Scholar
  4. 4.
    Hesterkamp T, Whittaker M (2008) Curr Opin Chem Biol 12:260–268CrossRefGoogle Scholar
  5. 5.
    Erlanson DA, Wells JA, Braisted AC (2004) Annu Rev Biophys Biomol Struct 33:199–223CrossRefGoogle Scholar
  6. 6.
    Rees DC, Congreve M, Murray CW, Carr R (2004) Nat Rev Drug Discov 3:660–672CrossRefGoogle Scholar
  7. 7.
    Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) J Med Chem 51:3661–3680CrossRefGoogle Scholar
  8. 8.
    Congreve M, Carr R, Murray C, Jhoti H (2003) Drug Discov Today 8:876–877CrossRefGoogle Scholar
  9. 9.
    Zartler ER, Shapiro MJ (2005) Curr Opin Chem Biol 9:366–370CrossRefGoogle Scholar
  10. 10.
    Siegal G, Ab E, Schultz J (2007) Drug Discov Today 12:1032–1039CrossRefGoogle Scholar
  11. 11.
    Shuker SB, Hajduk PJ, Meadows RP, Fesik SW (1996) Science 274:1531–1534CrossRefGoogle Scholar
  12. 12.
    Hadjuk PJ, Meadows RP, Fesik SW (1999) Quart Rev Biophys 32:211–240CrossRefGoogle Scholar
  13. 13.
    Jhoti H, Cleasby A, Vedonk M, Williams G (2007) Curr Opin Chem Biol 11:485–493CrossRefGoogle Scholar
  14. 14.
    Carr R, Jhoti H (2002) Drug Discov Today 7:522–527CrossRefGoogle Scholar
  15. 15.
    Hartshorn MJ, Murray CW, Cleabsy A, Frederickson M, Tickle IJ, Jhoti H (2005) J Med Chem 48:403–413CrossRefGoogle Scholar
  16. 16.
    Murray CW, Blundell TL (2010) Curr Opin Struct Biol 20:497–507CrossRefGoogle Scholar
  17. 17.
    Davies TG, Tickle IJ (2011) Fragment screening using X-ray crystallography. Top Curr Chem. doi: 10.1007/128_179
  18. 18.
    Navratilova I, Hopkins A (2010) ACS Med Chem Lett 1:44–48CrossRefGoogle Scholar
  19. 19.
    Neumann T, Junker HD, Schmidt K, Sekul R (2007) Curr Top Med Chem 7:1630–42CrossRefGoogle Scholar
  20. 20.
    Huber W, Mueller F (2006) Curr Pharm Des 12:3999–4021CrossRefGoogle Scholar
  21. 21.
    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_225
  22. 22.
    Zartler ER, Shapiro MJ (2008) In: Zartler ER, Shapiro MJ (eds) Fragment-based drug discovery: a practical approach. Wiley, United KingdomCrossRefGoogle Scholar
  23. 23.
    Torres FE, Recht MI, Coyle JE, Bruce RH, Williams G (2010) Curr Opin Struct Biol 20:598–605CrossRefGoogle Scholar
  24. 24.
    Ladbury JE, Klebe G, Freire E (2010) Nat Rev Drug Discov 9:23–27CrossRefGoogle Scholar
  25. 25.
    Robins T, Plattner J (1993) J Acq Immun Def Syn 6:162–170Google Scholar
  26. 26.
    Kempf DJ, Sham HL (1996) Curr Pharm Des 2:225–246Google Scholar
  27. 27.
    Abdel-Rahman HM, Al-karamany GS, El-Koussi NA, Youssef AF, Kiso Y (2002) Curr Med Chem 9:1905–1922Google Scholar
  28. 28.
    Huff JR (1991) J Med Chem 34:2305–2314CrossRefGoogle Scholar
  29. 29.
    Perryman AL, Lin JH, McCammon JA (2004) Prot Sci 13:1108–1123CrossRefGoogle Scholar
  30. 30.
    Perryman A, Zhang Q, Soutter HH, Rosenfeld R, McRee DE, Olson AJ, Elder JE, Stout CD (2010) Chem Biol Drug Des 75:257–268CrossRefGoogle Scholar
  31. 31.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Science 256:1783–1790CrossRefGoogle Scholar
  32. 32.
    Jacobo-Molina A, Ding J, Nanni RG, Clark AD, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P (1993) Proc Natl Acad Sci USA 90:6320–6324CrossRefGoogle Scholar
  33. 33.
    Jochmans D, Deval J, Kesteleyn B, Van Marck H, Bettens E, De Baere I, Dehertogh P, Ivens T, Van Ginderen M, Van Schoubroeck B, Ehteshami M, Wigerinck P, Götte M, Hertogs K (2006) J Virol 80:12283–12292CrossRefGoogle Scholar
  34. 34.
    Camarasa M-J, Velázquez S, San-Félix A, Pérez-Pérez MJ (2005) Antivir Chem Chemother 16:147–153Google Scholar
  35. 35.
    Tramontano E, Di Santo R (2010) Curr Med Chem 17:2837–2853CrossRefGoogle Scholar
  36. 36.
    Götte M, Rausch JW, Marchand B, Sarafianos S, Le Grice SFJ (2010) Biochim Biophys Acta 1804:1202–1212Google Scholar
  37. 37.
    Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH, Arnold E (2009) J Mol Biol 385:693–713CrossRefGoogle Scholar
  38. 38.
    Bauman JD, Das K, Ho WC, Baweja M, Himmel DM, Clark AD, Oren DA, Boyer PL, Hughes SH, Shatkin AJ, Arnold E (2008) Nucleic Acids Res 36:5083–5092CrossRefGoogle Scholar
  39. 39.
    Verlinde CLMJ, Fan E, Shibata S, Zhang Z, Sun Z, Deng W, Ross J, Kim J, Xiao L, Arakaki T, Bosch J, Caruthers JM, Larson ET, LeTrong I, Napuli A, Kelley A, Mueller N, Zucker F, Van Voorhis WC, Buckner FS, Merritt EA, Hol WGJ (2009) Curr Top Med Chem 9:1678–1687CrossRefGoogle Scholar
  40. 40.
    Ballester PJ, Richards WG (2007) J Comput Chem 28:1711–1723CrossRefGoogle Scholar
  41. 41.
    Blaney J, Nienaber V, Burley SK (2006) In: Jahnke W, Erlanson DA (eds) Fragment-based Approaches in Drug Discovery. Wiley-VCH Verlag GmbH & Co. KGaAGoogle Scholar
  42. 42.
    Gietmann M, Elinder M, Seeger C, Brandt P, de Esch IJP, Danielson UH (2011) J Med Chem 54:699–708CrossRefGoogle Scholar
  43. 43.
    Brandt P, Geitmann M, Danielson UH (2011) J Med Chem 54:709–718CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Department of Medicinal ChemistryRutgers UniversityPiscatawayUSA

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