Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

  • Wan F. Lau
  • Jane M. Withka
  • David Hepworth
  • Thomas V. Magee
  • Yuhua J. Du
  • Gregory A. Bakken
  • Michael D. Miller
  • Zachary S. Hendsch
  • Venkataraman Thanabal
  • Steve A. Kolodziej
  • Li Xing
  • Qiyue Hu
  • Lakshmi S. Narasimhan
  • Robert Love
  • Maura E. Charlton
  • Samantha Hughes
  • Willem P. van Hoorn
  • James E. Mills


Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM–mM hits and the uniqueness of hits at weak binding affinities for these targets.


Fragment screening Fragment based drug design Library design Chemical diversity Chemical space 

Supplementary material

10822_2011_9434_MOESM1_ESM.doc (602 kb)
Supplementary material 1 (DOC 601 kb)


  1. 1.
    Congreve M, Chessari G, Tisi D, Woodhead A (2008) J Med Chem 51:3661CrossRefGoogle Scholar
  2. 2.
    Albert J, Blomberg N, Breeze A, Brown A, Burrows J, Edwards P, Folmer R, Geschwindner S, Griffen E, Kenny P, Nowak T, Olsson L, Sanganee H, Shapiro A (2007) Curr Topics Med Chem 7:1600CrossRefGoogle Scholar
  3. 3.
    Shuker S, Hajduk P, Meadows R, Fesik S (1996) Science 274:1531CrossRefGoogle Scholar
  4. 4.
    Lepre C, Peng J, Fejzo J, Abdul-Manan N, Pocas J, Jacobs M, Xie X, Moore J (2002) Comb Chem High Throughput Screen 5:583Google Scholar
  5. 5.
    Lipinski C, Lombardo F, Dominy B, Feeney P (2001) Adv Drug Deliv Rev 46:3CrossRefGoogle Scholar
  6. 6.
    Carr R, Congreve M, Murray C, Rees D (2005) Drug Discov Today 10:987CrossRefGoogle Scholar
  7. 7.
    Hopkins A, Groom C, Alex A (2004) Drug Discov Today 9:430CrossRefGoogle Scholar
  8. 8.
    Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray C, Searvers L, van Montfort R (2006) J Med Chem 49:1346CrossRefGoogle Scholar
  9. 9.
    Saxty G, Woodhead S, Berdini V, Davies T, Verdonk M, Wyatt P, Boyle R, Barford D, Downham R, Garrett M, Carr R (2007) J Med Chem 50:2293CrossRefGoogle Scholar
  10. 10.
    Hajduk P, Huth J, Tse C (2005) Drug Discov Today 10:1675CrossRefGoogle Scholar
  11. 11.
    Baurin N, Aboul-Ela F, Barril X, Davis B, Drysdale M, Dymock B, Finch H, Fromont C, Richardson C, Simmonite H, Hubbard RE (2004) J Chem Inf Comp Sci 44:2157Google Scholar
  12. 12.
    Blomberg N, Cosgrove DA, Kenny PW, Kolmodin K (2009) J Comput Aided Mol Des 23:513CrossRefGoogle Scholar
  13. 13.
    Schuffenhauer A, Ruedisser S, Marzinzik AL, Jahnke W, Blommers M, Selzer P, Jacoby E (2005) Curr Topics Med Chem 5:751CrossRefGoogle Scholar
  14. 14.
    Leach A, Hann M, Burrows J, Griffen E (2006) Structure-based drug discovery. Royal Society of Chemistry, CambridgeGoogle Scholar
  15. 15.
    Lepre C (2001) DDT 6:133Google Scholar
  16. 16.
    Erlanson D, McDowell R, O’Brien T (2004) J Med Chem 47:3463CrossRefGoogle Scholar
  17. 17.
    Fattori D, Squarcia A, Bartoli S (2008) Drugs R D 9:217CrossRefGoogle Scholar
  18. 18.
    Barker J, Courtney S, Hesterkamp T, Ullmann D, Whittaker M (2006) Expert Opin Drug Discov 1:225CrossRefGoogle Scholar
  19. 19.
    Mayer M, Meyer B (1999) Angew Chem Int Ed 38:1784CrossRefGoogle Scholar
  20. 20.
    Dalvit C, Fogliatto G, Stewart A, Veronest M, Stockman B (2001) J Biomol NMR 21:349CrossRefGoogle Scholar
  21. 21.
    Wang Y, Liu D, Wyss D (2004) Magn Reson Chem 42:485CrossRefGoogle Scholar
  22. 22.
    Hartshorn M, Murray C, Cleasby A, Frederickson M, Tickle I, Jhoti H (2005) J Med Chem 48:403CrossRefGoogle Scholar
  23. 23.
    Hubbard R, Davies B, Chen I, Drysdale M (2007) Curr Topics Med Chem 7:1568CrossRefGoogle Scholar
  24. 24.
    Neumann T, Junker H, Schmidt K, Sekul R (2007) Curr Topics Med Chem (Sharjah, United Arab Emirates) 7:1630Google Scholar
  25. 25.
    Hubbard R, Chen I, Davies B (2007) Curr Opin Drug Discov Dev 10:289Google Scholar
  26. 26.
    Card G, Blasdel L, England B, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim P, Artis D, Bollag G, Milburn M, Kim S, Schlessinger J, Zhang K (2005) Nat Biotechnol 23:201CrossRefGoogle Scholar
  27. 27.
    Jhoti H, Cleasby A, Verdonk M, Williams G (2007) Curr Opin Chem Biol 11:485CrossRefGoogle Scholar
  28. 28.
    Hann M, Leach A, Harper G (2001) J Chem Inf Comp Sci 41:856Google Scholar
  29. 29.
    Schuffenhauer A, Floersheim P, Acklin P, Jacoby E (2003) J Chem Inf Comp Sci 43:391Google Scholar
  30. 30.
    Hu Q, Peng Z, Kostrowicki J, Kuki A (2010) In: Zhou Z, Walter J (eds) Chemical library design in methods in molecular biology (MiMB) series. Humana Press, New York, pp 253–276Google Scholar
  31. 31.
    Congreve M, Carr R, Murray C, Jhoti H (2003) Drug Discov Today 8:876CrossRefGoogle Scholar
  32. 32.
    Ladbury J, Klebe G, Freire E (2010) Nat Rev Drug Discov 9:23CrossRefGoogle Scholar
  33. 33.
    Burrows J (2004) Soc Med Res Trends Drug DiscovGoogle Scholar
  34. 34.
    WOMBAT (2005) Santa Fe available at:
  35. 35.
    Oprea T, Blaney J (2006) In: Jahnke W, Erlanson DA (eds) Fragment-based approaches in drug discovery, pp 91–111Google Scholar
  36. 36.
    Njardarson Group, Kwon L, Rogers E, McGrath N, Brichacek M, Njarðarson J (2006) Available at:
  37. 37.
    Teague SJ, Davis AM, Leeson PD, Oprea TI (1999) Angew Chem Int Ed 38:3743CrossRefGoogle Scholar
  38. 38.
    Allu T, Oprea T (2005) J Chem Inf Model 45:1237CrossRefGoogle Scholar
  39. 39.
    Reynolds C, Tounge B, Bembenek S (2008) J Med Chem 51:2432CrossRefGoogle Scholar
  40. 40.
    Irwin J, Shoichet B (2005) J Chem Inf Model 45:177CrossRefGoogle Scholar
  41. 41.
    Zhou J, Shi S, Na J, Peng Z, Thacher T (2009) J Comput Aided Mol Des 23:725CrossRefGoogle Scholar
  42. 42.
    Ertl P, Rohde B, Selzer P (2000) J Med Chem 43:3714CrossRefGoogle Scholar
  43. 43.
    Gao SVH, Lee P (2002) Pharm Res 19:497CrossRefGoogle Scholar
  44. 44.
    Leadscope, Inc., 1393 Dublin Road, Columbus, OH 43215Google Scholar
  45. 45.
    Roberts G, Myatt G, Johnson W, Cross K, Blower P (2000) J Chem Inf Comput Sci 40:1302Google Scholar
  46. 46.
    Daylight Chemical Information Systems Inc In: Aliso Viejo, CA 92656, USAGoogle Scholar
  47. 47.
    Ward J (1963) J Am Stat Assoc 58:236CrossRefGoogle Scholar
  48. 48.
    PipelinePilot In: 10188 Telesis Court, Suite 100, San Diego, CA 92121-4779Google Scholar
  49. 49.
    Durant J, Leland B, Henry D, Nourse J (2002) J Chem Inf Comput Sci 42:1273Google Scholar
  50. 50.
    Bemis G, Murcko M (1996) J Med Chem 39:2887CrossRefGoogle Scholar
  51. 51.
    Corina Inc In: molecular-networks GmbHGoogle Scholar
  52. 52.
    Murral N, Davies E (1990) J Chem Inf Comp Sci 30:312Google Scholar
  53. 53.
    Mills J, Dean P (1996) J Comput Aided Mol Des 10:607CrossRefGoogle Scholar
  54. 54.
    Bakken G, Du J, Li D, Lu J, Schulte G, Sridaharan S, Tinniswood A, Miller M (2006)Google Scholar
  55. 55.
    Paolini G, Shapland R, van Hoorn W, Mason J, Hopkins A (2006) Nat Biotechnol 24:805CrossRefGoogle Scholar
  56. 56.
    Gasteiger J, Rudolph C, Sadowski J (2004) Tetrahedron Comput Methodol 3:537CrossRefGoogle Scholar
  57. 57.
    ROCS OpenEye Scientific Software In: Santa Fe, New Mexico, USAGoogle Scholar
  58. 58.
    Jakes S, Willet P (1986) J. Mol. Graphics 4:12CrossRefGoogle Scholar
  59. 59.
    Davies K, Briant C (1995) In: MGMS meeting, LeedsGoogle Scholar
  60. 60.
    Stockman B, Lodovice I, Fisher D, McColl A, Xie Z (2007) J Biomol Screen 12:457CrossRefGoogle Scholar
  61. 61.
    Hu Q, Yan J, Withka J, Sahasrabudhe P, Moore C, Na J, Narasimhan L (2009) Abstracts of papers, 238th ACS National Meeting, Washington, DC, USAGoogle Scholar
  62. 62.
    Chen I, Hubbard R (2009) J Comput Aided Mol Des 23:603CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Wan F. Lau
    • 1
  • Jane M. Withka
    • 1
  • David Hepworth
    • 1
  • Thomas V. Magee
    • 1
  • Yuhua J. Du
    • 2
  • Gregory A. Bakken
    • 1
  • Michael D. Miller
    • 1
  • Zachary S. Hendsch
    • 1
  • Venkataraman Thanabal
    • 1
  • Steve A. Kolodziej
    • 3
  • Li Xing
    • 4
  • Qiyue Hu
    • 5
  • Lakshmi S. Narasimhan
    • 5
  • Robert Love
    • 5
  • Maura E. Charlton
    • 4
  • Samantha Hughes
    • 6
  • Willem P. van Hoorn
    • 7
  • James E. Mills
    • 6
  1. 1.Pfizer Global Research and Development (PGRD)GrotonUSA
  2. 2.PTC Therapeutic, Inc.South PlainfieldUSA
  3. 3.Pfizer Global Research and Development (PGRD)Saint LouisUSA
  4. 4.Pfizer Global Research and Development (PGRD)CambridgeUSA
  5. 5.Pfizer Global Research and Development (PGRD)La JollaUSA
  6. 6.Pfizer Global Research and Development (PGRD)SandwichUK
  7. 7.Accelrys LtdCambridgeUK

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