Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 603–620 | Cite as

Lessons for fragment library design: analysis of output from multiple screening campaigns

Article

Abstract

Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library.

Keywords

Fragment screening Fragment based drug discovery Library design Chemical space 

Abbreviations

AK

Adenosine kinase

CDK2

Cyclin-dependent kinase 2

DNAG

DNA gyrase

FAAH

Fatty acid amide hydrolase

HSP70

Human heat shock protein 70

HSP90

Human heat shock protein 90

JNK3

c-Jun N-terminal kinase 3

PDPK1

3-Phosphoinositide-dependent protein kinase 1

PIN-1

Peptidyl-prolyl cis/trans isomerase

PPI

Protein–protein interaction

SeeDs

Structural exploitation of experimental drug startpoints

Supplementary material

10822_2009_9280_MOESM1_ESM.doc (64 kb)
(DOC 64 kb)

References

  1. 1.
    Hajduk PJ, Greer J (2007) Nat Rev Drug Discov 6:211. doi:10.1038/nrd2220 CrossRefGoogle Scholar
  2. 2.
    Jhoti H, Cleasby A, Verdonk M, Williams G (2007) Curr Opin Chem Biol 11:485. doi:10.1016/j.cbpa.2007.07.010 CrossRefGoogle Scholar
  3. 3.
    Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) J Med Chem 51:3661. doi:10.1021/jm8000373 CrossRefGoogle Scholar
  4. 4.
    Shuker SB, Hajduk PJ, Meadows RP, Fesik SW (1996) Science 274:1531. doi:10.1126/science.274.5292.1531 CrossRefGoogle Scholar
  5. 5.
    Nienaber VL, Richardson PL, Klighofer V, Bouska JJ, Giranda VL, Greer J (2000) Nat Biotechnol 18:1105. doi:10.1038/80319 CrossRefGoogle Scholar
  6. 6.
    Lepre CA, Moore JM, Peng JW (2004) Chem Rev 104:3641. doi:10.1021/cr030409h CrossRefGoogle Scholar
  7. 7.
    Antonysamy SS, Aubol B, Blaney J, Browner MF, Giannetti AM, Harris SF, Hébert N, Hendle J, Hopkins S, Jefferson E, Kissinger C, Leveque V, Marciano D, McGee E, Nájera I, Nolan B, Tomimoto M, Torres E, Wright T (2008) Bioorg Med Chem Lett 18:2990. doi:10.1016/j.bmcl.2008.03.056 CrossRefGoogle Scholar
  8. 8.
    Hubbard RE, Davis B, Chen I, Drysdale MJ (2007) Curr Top Med Chem 7:1568. doi:10.2174/156802607782341109 CrossRefGoogle Scholar
  9. 9.
    Mayer M, Meyer B (1999) Angew Chem Int Ed Engl 38:1784. doi:10.1002/(SICI)1521-3773(19990614)38:12<1784::AID-ANIE1784>3.0.CO;2-Q CrossRefGoogle Scholar
  10. 10.
    Meiboom S, Gill D (1958) Rev Sci Instrum 29:688. doi:10.1063/1.1716296 CrossRefGoogle Scholar
  11. 11.
    Dalvit P, Pevarello DP, Tato M, Veronesi M, Vulpetti A, Sundstrom M, Bio J (2000) NMR 18:65. doi:10.1023/A:1008354229396 CrossRefGoogle Scholar
  12. 12.
    Petros AM, Dinges J, Augeri DJ, Baumeister SA, Betebenner DA, Bures MG, Elmore SW, Hajduk PJ, Joseph MK, Landis SK, Nettesheim DG, Rosenberg SH, Shen W, Thomas S, Wang X, Zanze I, Zhang H, Fesik SW (2006) J Med Chem 49:656. doi:10.1021/jm0507532 CrossRefGoogle Scholar
  13. 13.
    Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LCA, van Montfort RLM (2006) J Med Chem 49:1346. doi:10.1021/jm050850v CrossRefGoogle Scholar
  14. 14.
    Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung K-MJ, Collins I, Davies NGM, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L (2008) J Med Chem 51:196. doi:10.1021/jm701018h CrossRefGoogle Scholar
  15. 15.
    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 Comput Sci 44:2157. doi:10.1021/ci049806z Google Scholar
  16. 16.
    Jacoby E, Davies J, Blommers MJJ (2003) Curr Top Med Chem 3:11. doi:10.2174/1568026033392606 CrossRefGoogle Scholar
  17. 17.
    Rees DC, Congreve M, Murray CW, Carr R (2004) Nat Rev Drug Discov 3:660. doi:10.1038/nrd1467 CrossRefGoogle Scholar
  18. 18.
    Schuffenhauer A, Ruedisser S, Marzinzik AL, Jahnke W, Blommers M, Selzer P, Jacoby E (2005) Curr Top Med Chem 5:751. doi:10.2174/1568026054637700 CrossRefGoogle Scholar
  19. 19.
    Albert JS, Blomberg N, Breeze AL, Brown AJ, Burrows JN, Edwards PD, Folmer RH, Geschwindner S, Griffen EJ, Kenny PW, Nowak T, Olsson LL, Sanganee H, Shapiro AB (2007) Curr Top Med Chem 7:1600. doi:10.2174/156802607782341091 CrossRefGoogle Scholar
  20. 20.
    Hubbard RE, Chen I, Davis B (2007) Curr Opin Drug Discov Devel 10:289Google Scholar
  21. 21.
    Hajduk PJ, Bures M, Praestgaard J, Fesik SW (2000) J Med Chem 43:3443. doi:10.1021/jm000164q CrossRefGoogle Scholar
  22. 22.
    Muegge I, Heald SL, Brittelli D (2001) J Med Chem 44:1841. doi:10.1021/jm015507e CrossRefGoogle Scholar
  23. 23.
    Bemis GW, Murcko MA (1999) J Med Chem 42:5095. doi:10.1021/jm9903996 CrossRefGoogle Scholar
  24. 24.
    Bemis JW, Murcko MA (1996) J Med Chem 39:2887. doi:10.1021/jm9602928 CrossRefGoogle Scholar
  25. 25.
  26. 26.
    Furet P, Meyer T, Strauss A, Raccuglia S, Rondeau J-M (2002) Bioorg Med Chem Lett 12:221. doi:10.1016/S0960-894X(01)00715-6 CrossRefGoogle Scholar
  27. 27.
    Thomson Scientific 3501 Market Street, Philadelphia, PA 19104, U.S.A., http://thomsonderwent.com/products/lr/wdi/
  28. 28.
    MOE (The Molecular Operating Environment) Version 2008.10, Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montreal, Canada H3A 2R7. http://www.chemcomp.com
  29. 29.
    Kirsten G (2008) GpiDAPH3, Chemical computing group, personal communicationGoogle Scholar
  30. 30.
  31. 31.
    Jarvis RA, Patrick EA (1973) Trans IEEE Comput C-22:1025CrossRefGoogle Scholar
  32. 32.
    Durant JL, Leland BA, Henry DR, Nourse JG (2002) J Chem Inf Comput Sci 42:1273. doi:10.1021/ci010132r Google Scholar
  33. 33.
    MACCS (Molecular ACCess System) Symyx Technologies, Inc, 415 Oakmead Parkway, Sunnyvale, CA 94085Google Scholar
  34. 34.
    SiteMap 2.2 (2008) Schrodinger LLC, 120 West 45th Street, New York, NY 10036Google Scholar
  35. 35.
    Halgren TA (2009) J Chem Inf Model 49:377. doi:10.1021/ci800324m CrossRefGoogle Scholar
  36. 36.
    Protein Preparation Wizard (2008) Schrodinger LLC, 120 West 45th Street, New York, NY 10036Google Scholar
  37. 37.
    Schuffenhauer A, Ertl P, Roggo S, Wetzel S, Koch MA, Waldmann H (2007) J Chem Inf Model 47:47. doi:10.1021/ci600338x CrossRefGoogle Scholar
  38. 38.
    Fejzo J, Lepre CA, Peng JW, Bemis GW, Ajay, Murcko MA, Moore JM (1999) Chem Biol 6:755. doi:10.1016/S1074-5521(00)80022-8 CrossRefGoogle Scholar
  39. 39.
    Ertl P, Jelfs S, Muhlbacher J, Schuffenhauer A, Selzer P (2006) J Med Chem 49:4568. doi:10.1021/jm060217p CrossRefGoogle Scholar
  40. 40.
    Broughton HB, Watson IA (2005) J Mol Graph Model 23:51. doi:10.1016/j.jmgm.2004.03.016 CrossRefGoogle Scholar
  41. 41.
    Stahura FL, Xue L, Godden JW, Bajorath J (1999) J Mol Graph Model 17:1. doi:10.1016/S1093-3263(99)00015-7 CrossRefGoogle Scholar
  42. 42.
    Hopkins AL, Groom CR (2002) Nat Rev Drug Discov 1:727. doi:10.1038/nrd892 CrossRefGoogle Scholar
  43. 43.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Adv Drug Deliv Rev 23:3. doi:10.1016/S0169-409X(96)00423-1 CrossRefGoogle Scholar
  44. 44.
    Roche O, Kiyama R, Brooks CL (2001) J Med Chem 44:3592. doi:10.1021/jm000467k CrossRefGoogle Scholar
  45. 45.
    Chen X, Lin Y, Liu M, Gilson MK (2002) Bioinformatics 18:130. doi:10.1093/bioinformatics/18.1.130 CrossRefGoogle Scholar
  46. 46.
    Wang R, Fang X, Lu Y, Wang S (2004) J Med Chem 47:2977. doi:10.1021/jm030580l CrossRefGoogle Scholar
  47. 47.
    Wang R, Fang X, Lu Y, Yang C-Y, Wang S (2005) J Med Chem 48:4111. doi:10.1021/jm048957q CrossRefGoogle Scholar
  48. 48.
    Hu L, Benson ML, Smith RD, Lerner MG, Carlson HA (2005) Proteins 60:333. doi:10.1002/prot.20512 CrossRefGoogle Scholar
  49. 49.
    Kellenberger E, Muller P, Schalon C, Bret G, Foata N, Rognan D (2006) J Chem Inf Model 46:717. doi:10.1021/ci050372x CrossRefGoogle Scholar
  50. 50.
    Block P, Sottrifer CA, Dramburg I, Klebe G (2006) Nucleic Acids Res 34:D522. doi:10.1093/nar/gkj039 CrossRefGoogle Scholar
  51. 51.
    Smith RD, Hu L, Falkner JA, Benson ML, Nerothin JP, Carlson HA (2006) J Mol Graph Model 24:414. doi:10.1016/j.jmgm.2005.08.002 CrossRefGoogle Scholar
  52. 52.
    Carlson HA, Smith RD, Khazanov NA, Kirchhoff PD, Dunbar JB Jr, Benson ML (2008) J Med Chem 51:6432. doi:10.1021/jm8006504 CrossRefGoogle Scholar
  53. 53.
    Miranker A, Karplus M (1991) Proteins 11:29. doi:10.1002/prot.340110104 CrossRefGoogle Scholar
  54. 54.
    Laskowski RA (1995) J Mol Graph 13:323. doi:10.1016/0263-7855(95)00073-9 CrossRefGoogle Scholar
  55. 55.
    Hendlich M, Rippmann F, Barnickel G (1997) J Mol Graph Model 15:359. doi:10.1016/S1093-3263(98)00002-3 CrossRefGoogle Scholar
  56. 56.
    Liang J, Edelsbrunner H, Fu P, Sudhakar PV, Subramaniam S (1998) Proteins 33:1. doi:10.1002/(SICI)1097-0134(19981001)33:1<1::AID-PROT1>3.0.CO;2-O CrossRefGoogle Scholar
  57. 57.
    Brady GP Jr, Stouten PF (2000) J Comput Aided Mol Des 14:383. doi:10.1023/A:1008124202956 CrossRefGoogle Scholar
  58. 58.
    An J, Totrov M, Abagyan R (2004) Genome Inf 15:31Google Scholar
  59. 59.
    Laurie AT, Jackson RM (2005) Bioinformatics 21:1908. doi:10.1093/bioinformatics/bti315 CrossRefGoogle Scholar
  60. 60.
    Coleman RG, Salzberg AC, Cheng AC (2006) J Chem Inf Model 46:2631. doi:10.1021/ci600229z CrossRefGoogle Scholar
  61. 61.
    Nayal M, Honig B (2006) Proteins 63:892. doi:10.1002/prot.20897 CrossRefGoogle Scholar
  62. 62.
    Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, Caffrey DR, Salzberg AC, Huang ES (2007) Nat Biotechnol 25:71. doi:10.1038/nbt1273 CrossRefGoogle Scholar
  63. 63.
    Halgren T (2007) Chem Biol Drug Des 69:146. doi:10.1111/j.1747-0285.2007.00483.x CrossRefGoogle Scholar
  64. 64.
    Landon MR, Lancia DR Jr, Yu J, Thiel SC, Vajda S (2007) J Med Chem 50:1231. doi:10.1021/jm061134b CrossRefGoogle Scholar
  65. 65.
    Harris R, Olson AJ, Goodsell DS (2007) Proteins 70:1506. doi:10.1002/prot.21645 CrossRefGoogle Scholar
  66. 66.
    Schalon C, Surgand JS, Kellenberger E, Rognan D (2008) Proteins 71:1755. doi:10.1002/prot.21858 CrossRefGoogle Scholar
  67. 67.
    Hajduk PJ, Huth JR, Tse C (2005) Drug Discov Today 10:1675. doi:10.1016/S1359-6446(05)03624-X CrossRefGoogle Scholar
  68. 68.
    Hajduk PJ, Huth JR, Fesik S (2005) J Med Chem 48:2518. doi:10.1021/jm049131r CrossRefGoogle Scholar
  69. 69.
    Hardy LW, Peet NP (2004) Drug Discov Today 9:117. doi:10.1016/S1359-6446(03)02969-6 CrossRefGoogle Scholar
  70. 70.
    Xin H, Bernal A, Amato FA, Pinhasov A, Kauffman J, Brenneman DE, Derian CK, Andrade-Gordon P, Plata-Saalaman CR, Ilyin SE (2004) J Biomol Screen 9:286. doi:10.1177/1087057104263533 CrossRefGoogle Scholar
  71. 71.
    Savchuk NP, Balakin KV, Tkachenko SE (2004) Curr Opin Chem Biol 8:412. doi:10.1016/j.cbpa.2004.06.003 CrossRefGoogle Scholar
  72. 72.
    Darvas F, Dorman G, Puskas LG, Bucsai A, Urge L (2004) Med Chem Res 13:643. doi:10.1007/s00044-004-0108-5 CrossRefGoogle Scholar
  73. 73.
    Whitty A, Kumaravel G (2006) Nat Chem Biol 2:112. doi:10.1038/nchembio0306-112 CrossRefGoogle Scholar
  74. 74.
    Hajduk PJ, Gomtsyan A, Didomenico S, Cowart M, Bayburt EK, Solomon L, Severin J, Smith R, Walter K, Holzman TF, Stewart A, McGaraughty S, Jarvis MF, Kowaluk EA, Fesik SW (2000) J Med Chem 43:4781. doi:10.1021/jm000373a CrossRefGoogle Scholar
  75. 75.
    Richardson CM, Nunns CL, Williamson DS, Parratt MJ, Dokurno P, Howes R, Borgognoni J, Drysdale MJ, Finch H, Hubbard RE, Jackson PS, Kierstan P, Lentzen G, Moore JD, Murray JB, Simmonite H, Surgenor AE, Torrance CJ (2007) Bioorg Med Chem Lett 17:3880. doi:10.1016/j.bmcl.2007.04.110 CrossRefGoogle Scholar
  76. 76.
    Angehrn P, Buchmann S, Funk C, Goetschi E, Gmuender H, Hebeisen P, Kostrewa D, Link H, Luebbers T, Masciadri R, Nielsen JE, Reindl P, Ricklin F, Schmitt-Hoffmann A, Theil F-P (2004) J Med Chem 47:1487. doi:10.1021/jm0310232 CrossRefGoogle Scholar
  77. 77.
    Seierstad M, Breitenbucher JG (2008) J Med Chem 51:7327. doi:10.1021/jm800311k CrossRefGoogle Scholar
  78. 78.
    Zhao H, Serby MD, Xin Z, Szczepankiewicz BG, Liu M, Kosogof C, Liu B, Nelson LTJ, Johnson EF, Wang S, Pederson T, Gum RJ, Clampit JE, Haasch DL, Abad-Zapatero C, Fry EH, Rondinone C, Trevillyan JM, Sham HL, Liu G (2006) J Med Chem 49:4455. doi:10.1021/jm060465l CrossRefGoogle Scholar
  79. 79.
    Gopalsamy A, Shi M, Boschelli DH, Williamson R, Olland A, Hu Y, Krishnamurthy G, Han X, Arndt K, Guo B (2007) J Med Chem 50:5547. doi:10.1021/jm070851i CrossRefGoogle Scholar
  80. 80.
    Ranganathan R, Lu K, Hunter T, Noel J (1997) Cell 89:875. doi:10.1016/S0092-8674(00)80273-1 CrossRefGoogle Scholar
  81. 81.
    Bayer E, Goettsch S, Mueller J, Griewel B, Guiberman E, Mayr L, Bayer P (2003) J Biol Chem 278:26183. doi:10.1074/jbc.M300721200 CrossRefGoogle Scholar
  82. 82.
    Zhang Y, Daum S, Wildemann D, Zhou XZ, Verdecia MA, Bowman ME, Lucke C, Hunter T, Lu K-P, Fischer G, Noel JP (2007) ACS Chem Biol 2:320. doi:10.1021/cb7000044 CrossRefGoogle Scholar
  83. 83.
    Ruppert J, Welch W, Jain AN (1997) Protein Sci 6:524CrossRefGoogle Scholar
  84. 84.
    Sotriffer C, Klebe G (2002) Farmaco 57:243. doi:10.1016/S0014-827X(02)01211-9 CrossRefGoogle Scholar
  85. 85.
    Campbell SJ, Gold ND, Jackson RM, Westhead DR (2003) Curr Opin Struct Biol 13:389. doi:10.1016/S0959-440X(03)00075-7 CrossRefGoogle Scholar
  86. 86.
    Wang R, Fu Y, Lai L (1997) J Chem Inf Comput Sci 37:615. doi:10.1021/ci960169p Google Scholar
  87. 87.
    Oprea TI (2000) J Comput Aided Mol Des 14:251. doi:10.1023/A:1008130001697 CrossRefGoogle Scholar
  88. 88.
    Ertl P (2003) J Chem Inf Comput Sci 43:374. doi:10.1021/ci0255782 Google Scholar
  89. 89.
    Wildman SA, Crippen GM (1999) J Chem Inf Comput Sci 39:868. doi:10.1021/ci990307l Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Vernalis (R&D) LtdCambridgeUK
  2. 2.YSBL and HYMSUniversity of YorkYorkUK

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