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

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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.

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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

References

  1. Hajduk PJ, Greer J (2007) Nat Rev Drug Discov 6:211. doi:10.1038/nrd2220

    Article  CAS  Google Scholar 

  2. Jhoti H, Cleasby A, Verdonk M, Williams G (2007) Curr Opin Chem Biol 11:485. doi:10.1016/j.cbpa.2007.07.010

    Article  CAS  Google Scholar 

  3. Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) J Med Chem 51:3661. doi:10.1021/jm8000373

    Article  CAS  Google Scholar 

  4. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW (1996) Science 274:1531. doi:10.1126/science.274.5292.1531

    Article  CAS  Google Scholar 

  5. Nienaber VL, Richardson PL, Klighofer V, Bouska JJ, Giranda VL, Greer J (2000) Nat Biotechnol 18:1105. doi:10.1038/80319

    Article  CAS  Google Scholar 

  6. Lepre CA, Moore JM, Peng JW (2004) Chem Rev 104:3641. doi:10.1021/cr030409h

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  8. Hubbard RE, Davis B, Chen I, Drysdale MJ (2007) Curr Top Med Chem 7:1568. doi:10.2174/156802607782341109

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  10. Meiboom S, Gill D (1958) Rev Sci Instrum 29:688. doi:10.1063/1.1716296

    Article  CAS  Google Scholar 

  11. Dalvit P, Pevarello DP, Tato M, Veronesi M, Vulpetti A, Sundstrom M, Bio J (2000) NMR 18:65. doi:10.1023/A:1008354229396

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    CAS  Google Scholar 

  16. Jacoby E, Davies J, Blommers MJJ (2003) Curr Top Med Chem 3:11. doi:10.2174/1568026033392606

    Article  CAS  Google Scholar 

  17. Rees DC, Congreve M, Murray CW, Carr R (2004) Nat Rev Drug Discov 3:660. doi:10.1038/nrd1467

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  20. Hubbard RE, Chen I, Davis B (2007) Curr Opin Drug Discov Devel 10:289

    CAS  Google Scholar 

  21. Hajduk PJ, Bures M, Praestgaard J, Fesik SW (2000) J Med Chem 43:3443. doi:10.1021/jm000164q

    Article  CAS  Google Scholar 

  22. Muegge I, Heald SL, Brittelli D (2001) J Med Chem 44:1841. doi:10.1021/jm015507e

    Article  CAS  Google Scholar 

  23. Bemis GW, Murcko MA (1999) J Med Chem 42:5095. doi:10.1021/jm9903996

    Article  CAS  Google Scholar 

  24. Bemis JW, Murcko MA (1996) J Med Chem 39:2887. doi:10.1021/jm9602928

    Article  CAS  Google Scholar 

  25. http://www.daylight.com/dayhtml_tutorials/languages/smarts/index.html

  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

    Article  CAS  Google Scholar 

  27. Thomson Scientific 3501 Market Street, Philadelphia, PA 19104, U.S.A., http://thomsonderwent.com/products/lr/wdi/

  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. Kirsten G (2008) GpiDAPH3, Chemical computing group, personal communication

  30. http://accelrys.com/products/scitegic/

  31. Jarvis RA, Patrick EA (1973) Trans IEEE Comput C-22:1025

    Article  Google Scholar 

  32. Durant JL, Leland BA, Henry DR, Nourse JG (2002) J Chem Inf Comput Sci 42:1273. doi:10.1021/ci010132r

    CAS  Google Scholar 

  33. MACCS (Molecular ACCess System) Symyx Technologies, Inc, 415 Oakmead Parkway, Sunnyvale, CA 94085

  34. SiteMap 2.2 (2008) Schrodinger LLC, 120 West 45th Street, New York, NY 10036

  35. Halgren TA (2009) J Chem Inf Model 49:377. doi:10.1021/ci800324m

    Article  CAS  Google Scholar 

  36. Protein Preparation Wizard (2008) Schrodinger LLC, 120 West 45th Street, New York, NY 10036

  37. Schuffenhauer A, Ertl P, Roggo S, Wetzel S, Koch MA, Waldmann H (2007) J Chem Inf Model 47:47. doi:10.1021/ci600338x

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  39. Ertl P, Jelfs S, Muhlbacher J, Schuffenhauer A, Selzer P (2006) J Med Chem 49:4568. doi:10.1021/jm060217p

    Article  CAS  Google Scholar 

  40. Broughton HB, Watson IA (2005) J Mol Graph Model 23:51. doi:10.1016/j.jmgm.2004.03.016

    Article  CAS  Google Scholar 

  41. Stahura FL, Xue L, Godden JW, Bajorath J (1999) J Mol Graph Model 17:1. doi:10.1016/S1093-3263(99)00015-7

    Article  CAS  Google Scholar 

  42. Hopkins AL, Groom CR (2002) Nat Rev Drug Discov 1:727. doi:10.1038/nrd892

    Article  CAS  Google Scholar 

  43. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Adv Drug Deliv Rev 23:3. doi:10.1016/S0169-409X(96)00423-1

    Article  CAS  Google Scholar 

  44. Roche O, Kiyama R, Brooks CL (2001) J Med Chem 44:3592. doi:10.1021/jm000467k

    Article  CAS  Google Scholar 

  45. Chen X, Lin Y, Liu M, Gilson MK (2002) Bioinformatics 18:130. doi:10.1093/bioinformatics/18.1.130

    Article  CAS  Google Scholar 

  46. Wang R, Fang X, Lu Y, Wang S (2004) J Med Chem 47:2977. doi:10.1021/jm030580l

    Article  CAS  Google Scholar 

  47. Wang R, Fang X, Lu Y, Yang C-Y, Wang S (2005) J Med Chem 48:4111. doi:10.1021/jm048957q

    Article  CAS  Google Scholar 

  48. Hu L, Benson ML, Smith RD, Lerner MG, Carlson HA (2005) Proteins 60:333. doi:10.1002/prot.20512

    Article  CAS  Google Scholar 

  49. Kellenberger E, Muller P, Schalon C, Bret G, Foata N, Rognan D (2006) J Chem Inf Model 46:717. doi:10.1021/ci050372x

    Article  CAS  Google Scholar 

  50. Block P, Sottrifer CA, Dramburg I, Klebe G (2006) Nucleic Acids Res 34:D522. doi:10.1093/nar/gkj039

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  52. Carlson HA, Smith RD, Khazanov NA, Kirchhoff PD, Dunbar JB Jr, Benson ML (2008) J Med Chem 51:6432. doi:10.1021/jm8006504

    Article  CAS  Google Scholar 

  53. Miranker A, Karplus M (1991) Proteins 11:29. doi:10.1002/prot.340110104

    Article  CAS  Google Scholar 

  54. Laskowski RA (1995) J Mol Graph 13:323. doi:10.1016/0263-7855(95)00073-9

    Article  CAS  Google Scholar 

  55. Hendlich M, Rippmann F, Barnickel G (1997) J Mol Graph Model 15:359. doi:10.1016/S1093-3263(98)00002-3

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  57. Brady GP Jr, Stouten PF (2000) J Comput Aided Mol Des 14:383. doi:10.1023/A:1008124202956

    Article  CAS  Google Scholar 

  58. An J, Totrov M, Abagyan R (2004) Genome Inf 15:31

    CAS  Google Scholar 

  59. Laurie AT, Jackson RM (2005) Bioinformatics 21:1908. doi:10.1093/bioinformatics/bti315

    Article  CAS  Google Scholar 

  60. Coleman RG, Salzberg AC, Cheng AC (2006) J Chem Inf Model 46:2631. doi:10.1021/ci600229z

    Article  CAS  Google Scholar 

  61. Nayal M, Honig B (2006) Proteins 63:892. doi:10.1002/prot.20897

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  63. Halgren T (2007) Chem Biol Drug Des 69:146. doi:10.1111/j.1747-0285.2007.00483.x

    Article  CAS  Google Scholar 

  64. Landon MR, Lancia DR Jr, Yu J, Thiel SC, Vajda S (2007) J Med Chem 50:1231. doi:10.1021/jm061134b

    Article  CAS  Google Scholar 

  65. Harris R, Olson AJ, Goodsell DS (2007) Proteins 70:1506. doi:10.1002/prot.21645

    Article  CAS  Google Scholar 

  66. Schalon C, Surgand JS, Kellenberger E, Rognan D (2008) Proteins 71:1755. doi:10.1002/prot.21858

    Article  CAS  Google Scholar 

  67. Hajduk PJ, Huth JR, Tse C (2005) Drug Discov Today 10:1675. doi:10.1016/S1359-6446(05)03624-X

    Article  CAS  Google Scholar 

  68. Hajduk PJ, Huth JR, Fesik S (2005) J Med Chem 48:2518. doi:10.1021/jm049131r

    Article  CAS  Google Scholar 

  69. Hardy LW, Peet NP (2004) Drug Discov Today 9:117. doi:10.1016/S1359-6446(03)02969-6

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  71. Savchuk NP, Balakin KV, Tkachenko SE (2004) Curr Opin Chem Biol 8:412. doi:10.1016/j.cbpa.2004.06.003

    Article  CAS  Google Scholar 

  72. Darvas F, Dorman G, Puskas LG, Bucsai A, Urge L (2004) Med Chem Res 13:643. doi:10.1007/s00044-004-0108-5

    Article  CAS  Google Scholar 

  73. Whitty A, Kumaravel G (2006) Nat Chem Biol 2:112. doi:10.1038/nchembio0306-112

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  77. Seierstad M, Breitenbucher JG (2008) J Med Chem 51:7327. doi:10.1021/jm800311k

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  80. Ranganathan R, Lu K, Hunter T, Noel J (1997) Cell 89:875. doi:10.1016/S0092-8674(00)80273-1

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  83. Ruppert J, Welch W, Jain AN (1997) Protein Sci 6:524

    Article  CAS  Google Scholar 

  84. Sotriffer C, Klebe G (2002) Farmaco 57:243. doi:10.1016/S0014-827X(02)01211-9

    Article  CAS  Google Scholar 

  85. Campbell SJ, Gold ND, Jackson RM, Westhead DR (2003) Curr Opin Struct Biol 13:389. doi:10.1016/S0959-440X(03)00075-7

    Article  CAS  Google Scholar 

  86. Wang R, Fu Y, Lai L (1997) J Chem Inf Comput Sci 37:615. doi:10.1021/ci960169p

    CAS  Google Scholar 

  87. Oprea TI (2000) J Comput Aided Mol Des 14:251. doi:10.1023/A:1008130001697

    Article  CAS  Google Scholar 

  88. Ertl P (2003) J Chem Inf Comput Sci 43:374. doi:10.1021/ci0255782

    CAS  Google Scholar 

  89. Wildman SA, Crippen GM (1999) J Chem Inf Comput Sci 39:868. doi:10.1021/ci990307l

    CAS  Google Scholar 

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Acknowledgments

The authors thank many scientists at Vernalis to make the analysis possible. In particular, this analysis has benefit greatly from fruitful discussion and data mining by Heather Simmonite, Ben Davis and James Murray. We also express our gratitude to Chemical Computing Group and Schrodinger Inc., for answering our questions and helping us with the programs MOE and SiteMap to extract information needed for the analysis.

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Authors and Affiliations

  1. Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK

    I-Jen Chen & Roderick E. Hubbard

  2. YSBL and HYMS, University of York, York, YO10 5YW, UK

    Roderick E. Hubbard

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  1. I-Jen Chen
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Correspondence to Roderick E. Hubbard.

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Chen, IJ., Hubbard, R.E. Lessons for fragment library design: analysis of output from multiple screening campaigns. J Comput Aided Mol Des 23, 603–620 (2009). https://doi.org/10.1007/s10822-009-9280-5

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