Skip to main content

Advertisement

SpringerLink
Log in

The multiple roles of computational chemistry in fragment-based drug design

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Agnelli G, Haas S, Ginsberg JS, Krueger KA, Dmitrienko A, Brandt JT (2007) A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 5(4):746–753. doi:10.1111/j.1538-7836.2007.02436.x

    Article  CAS  Google Scholar 

  2. Albert JS (2007) Editorial: fragment-based drug discovery. Curr Top Med Chem 7(6):1543. doi:10.2174/156802607782341127

    Article  CAS  Google Scholar 

  3. Albert JS, Blomberg N, Breeze AL, Brown AJ, Burrows JN, Edwards PD, Folmer RH, Geschwindner S, Griffen EJ, Kenny PW et al (2007) An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca’s drug discovery programmes. Curr Top Med Chem 7(16):1600–1629. doi:10.2174/156802607782341091

    Article  CAS  Google Scholar 

  4. Alex AA, Flocco MM (2007) Fragment-based drug discovery: what has it achieved so far? Curr Top Med Chem 7(16):1544–1567. doi:10.2174/156802607782341082

    Article  CAS  Google Scholar 

  5. Artis DR, Lin JJ, Zhang C, Wang W, Mehra U, Perreault M, Erbe D, Krupka HI, England BP, Arnold J et al (2009) Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci USA 106(1):262–267. doi:10.1073/pnas.0811325106

    Article  Google Scholar 

  6. Babaoglu K, Shoichet BK (2006) Deconstructing fragment-based inhibitor discovery. Nat Chem Biol 2(12):720–723. doi:10.1038/nchembio831

    Article  CAS  Google Scholar 

  7. Barker J, Courtney S, Hesterkamp T, Ullmann D, Whittaker M (2006) Fragment screening by biochemical assay. Expert Opin Drug Discov 1(3):225–236. doi:10.1517/17460441.1.3.225

    Article  CAS  Google Scholar 

  8. Barker JJ, Barker O, Boggio R, Chauhan V, Cheng RKY, Corden V, Courtney SM, Edwards N, Falque VM, Fusar F, Gardiner M, Hamelin EMN, Hesterkamp T, Ichihara O, Jones RS, Mather O, Mercurio C, Minucci S, Montalbetti CAGN, Müller A, Patel D, Phillips BG, Varasi M, Whittaker M, Winkler D, Yarnold CJ (2009) Fragment-based Identification of Hsp90 Inhibitors. Chem Med Chem 4(6):963–966

    CAS  Google Scholar 

  9. Bartoli S, Fincham CI, Fattori D (2007) Fragment-based drug design: combining philosophy with technology. Curr Opin Drug Discov Devel 10(4):422–429

    CAS  Google Scholar 

  10. Baurin N, Aboul-Ela F, Barril X, Davis B, Drysdale M, Dymock B, Finch H, Fromont C, Richardson C, Simmonite H et al (2004) Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. J Chem Inf Comput Sci 44(6):2157–2166. doi:10.1021/ci049806z

    CAS  Google Scholar 

  11. Blaney J, Nienaber V, Burley SK (2006) Fragment based lead discovery optimization using X-ray crystallography, computational chemistry, and high throughput organic synthesis. Fragment-based approaches in drug discovery, vol 34. Wiley, Weinheim, pp 215–248

    Google Scholar 

  12. Boehm HJ, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W, Kostrewa D, Kuehne H, Luebbers T, Meunier-Keller N et al (2000) Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J Med Chem 43(14):2664–2674. doi:10.1021/jm000017s

    Article  CAS  Google Scholar 

  13. Bohm HJ (1992) The computer program LUDI: a new method for the de novo design of enzyme inhibitors. J Comput Aided Mol Des 6(1):61–78. doi:10.1007/BF00124387

    Article  CAS  Google Scholar 

  14. Brewer M, Ichihara O, Kirchoff C, Schade M, Whittaker M (2008) Assembling a fragment library. Fragment-based drug discovery; a practical approach. Wiley, Weinheim, pp 39–62

    Google Scholar 

  15. Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ et al (2008) 4, 5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51(2):196–218. doi:10.1021/jm701018h

    Article  CAS  Google Scholar 

  16. Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC et al (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50(4):641–662. doi:10.1021/jm061152t

    Article  CAS  Google Scholar 

  17. Carr RA, Congreve M, Murray CW, Rees DC (2005) Fragment-based lead discovery: leads by design. Drug Discov Today 10(14):987–992. doi:10.1016/S1359-6446(05)03511-7

    Article  CAS  Google Scholar 

  18. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, Fadden P, Partdrige J, Hall S, Steed P et al (2008) SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 14(1):240–248. doi:10.1158/1078-0432.CCR-07-1667

    Article  CAS  Google Scholar 

  19. Chappie TA, Humphrey JM, Allen MP, Estep KG, Fox CB, Lebel LA, Liras S, Marr ES, Menniti FS, Pandit J et al (2007) Discovery of a series of 6, 7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors. J Med Chem 50(2):182–185. doi:10.1021/jm060653b

    Article  CAS  Google Scholar 

  20. Ciulli A, Abell C (2007) Fragment-based approaches to enzyme inhibition. Curr Opin Biotechnol 18(6):489–496. doi:10.1016/j.copbio.2007.09.003

    Article  CAS  Google Scholar 

  21. Congreve M, Carr R, Murray C, Jhoti H (2003) A ‘rule of three’ for fragment-based lead discovery? Drug Discov Today 8(19):876–877. doi:10.1016/S1359-6446(03)02831-9

    Article  Google Scholar 

  22. Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) Recent developments in fragment-based drug discovery. J Med Chem 51(13):3661–3680. doi:10.1021/jm8000373

    Article  CAS  Google Scholar 

  23. Crisman TJ, Bender A, Milik M, Jenkins JL, Scheiber J, Sukuru SC, Fejzo J, Hommel U, Davies JW, Glick M (2008) “Virtual fragment linking”: an approach to identify potent binders from low affinity fragment hits. J Med Chem 51(8):2481–2491. doi:10.1021/jm701314u

    Article  CAS  Google Scholar 

  24. Crisman TJ, Sisay MT, Bajorath J (2008) Ligand-target interaction-based weighting of substructures for virtual screening. J Chem Inf Model 48(10):1955–1964. doi:10.1021/ci800229q

    Article  CAS  Google Scholar 

  25. Dai Y, Hartandi K, Ji Z, Ahmed AA, Albert DH, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KB et al (2007) Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem 50(7):1584–1597. doi:10.1021/jm061280h

    Article  CAS  Google Scholar 

  26. Das K, Lewi PJ, Hughes SH, Arnold E (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88(2):209–231. doi:10.1016/j.pbiomolbio.2004.07.001

    Article  CAS  Google Scholar 

  27. Dymock B, Barril X, Beswick M, Collier A, Davies N, Drysdale M, Fink A, Fromont C, Hubbard RE, Massey A et al (2004) Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures. Bioorg Med Chem Lett 14(2):325–328. doi:10.1016/j.bmcl.2003.11.011

    Article  CAS  Google Scholar 

  28. Eisen MB, Wiley DC, Karplus M, Hubbard RE (1994) HOOK: a program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site. Proteins 19(3):199–221. doi:10.1002/prot.340190305

    Article  CAS  Google Scholar 

  29. Erlanson DA (2006) Fragment-based lead discovery: a chemical update. Curr Opin Biotechnol 17(6):643–652. doi:10.1016/j.copbio.2006.10.007

    Article  CAS  Google Scholar 

  30. Fejzo J, Lepre CA, Peng JW, Bemis GW, Ajay MurckoMA, Moore JM (1999) The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. Chem Biol 6(10):755–769. doi:10.1016/S1074-5521(00)80022-8

    Article  CAS  Google Scholar 

  31. Fink T, Bruggesser H, Reymond JL (2005) Virtual exploration of the small-molecule chemical universe below 160 Daltons. Angew Chem Int Ed Engl 44(10):1504–1508. doi:10.1002/anie.200462457

    Article  CAS  Google Scholar 

  32. Foloppe N, Hubbard R (2006) Towards predictive ligand design with free-energy based computational methods? Curr Med Chem 13(29):3583–3608. doi:10.2174/092986706779026165

    Article  CAS  Google Scholar 

  33. Froning KJ, Felce JD, Jessen KA, Leonard S, Gutierrez A, Tang C, Huser N, Do T, Gessert S, Aubol B et al. (2007) SGX523: a potent and highly selective small molecule inhibitor of the MET receptor tyrosine kinase. http://www.sgxpharma.com/pipeline/documents/SGX523METAACR07.pdf

  34. Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, de Beer T, Folmer RH (2007) Discovery of a novel warhead against beta-secretase through fragment-based lead generation. J Med Chem 50(24):5903–5911. doi:10.1021/jm070825k

    Article  CAS  Google Scholar 

  35. Hajduk PJ (2005) Druggability indices for protein targets derived from NMR-based screening data. J Med Chem 48:2518–2525. doi:10.1021/jm049131r

    Article  CAS  Google Scholar 

  36. Hajduk PJ (2006) Fragment-based drug design: how big is too big? J Med Chem 49(24):6972–6976. doi:10.1021/jm060511h

    Article  CAS  Google Scholar 

  37. Hajduk PJ, Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6(3):211–219. doi:10.1038/nrd2220

    Article  CAS  Google Scholar 

  38. Hann MM, Leach AR, Harper G (2001) Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comput Sci 41(3):856–864. doi:10.1021/ci000403i

    CAS  Google Scholar 

  39. Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H (2005) Fragment-based lead discovery using X-ray crystallography. J Med Chem 48(2):403–413. doi:10.1021/jm0495778

    Article  CAS  Google Scholar 

  40. Hawkins PC, Skillman AG, Nicholls A (2007) Comparison of shape-matching and docking as virtual screening tools. J Med Chem 50(1):74–82. doi:10.1021/jm0603365

    Article  CAS  Google Scholar 

  41. Helgadottir A, Manolescu A, Helgason A, Thorleifsson G, Thorsteinsdottir U, Gudbjartsson DF, Gretarsdottir S, Magnusson KP, Gudmundsson G, Hicks A et al (2006) A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 38(1):68–74. doi:10.1038/ng1692

    Article  CAS  Google Scholar 

  42. Hesterkamp T, Whittaker M (2008) Fragment-based activity space: smaller is better. Curr Opin Chem Biol 12(3):260–268. doi:10.1016/j.cbpa.2008.02.005

    Article  CAS  Google Scholar 

  43. Hesterkamp T, Barker J, Davenport A, Whittaker M (2007) Fragment based drug discovery using fluorescence correlation: spectroscopy techniques: challenges and solutions. Curr Top Med Chem 7(16):1582–1591. doi:10.2174/156802607782341064

    Article  CAS  Google Scholar 

  44. Hofstadler SA, Sannes-Lowery KA (2006) Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes. Nat Rev Drug Discov 5(7):585–595. doi:10.1038/nrd2083

    Article  CAS  Google Scholar 

  45. Hopkins AL, Groom CR, Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9(10):430–431. doi:10.1016/S1359-6446(04)03069-7

    Article  Google Scholar 

  46. Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL et al (2009) Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 52(2):379–388. doi:10.1021/jm800984v

    Article  CAS  Google Scholar 

  47. Huang D, Caflisch A (2004) Efficient evaluation of binding free energy using continuum electrostatics solvation. J Med Chem 47(23):5791–5797. doi:10.1021/jm049726m

    Article  CAS  Google Scholar 

  48. Hubbard RE, Chen I, Davis B (2007) Informatics and modeling challenges in fragment-based drug discovery. Curr Opin Drug Discov Devel 10(3):289–297

    CAS  Google Scholar 

  49. Hubbard RE, Davis B, Chen I, Drysdale MJ (2007) The SeeDs approach: integrating fragments into drug discovery. Curr Top Med Chem 7(16):1568–1581. doi:10.2174/156802607782341109

    Article  CAS  Google Scholar 

  50. Huth JR, Park C, Petros AM, Kunzer AR, Wendt MD, Wang X, Lynch CL, Mack JC, Swift KM, Judge RA et al (2007) Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies. Chem Biol Drug Des 70(1):1–12. doi:10.1111/j.1747-0285.2007.00535.x

    Article  CAS  Google Scholar 

  51. Jahnke W, Erlanson DA (2007) Fragment-based approaches to lead discovery. Wiley, Weinheim

    Google Scholar 

  52. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E et al (2005) In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2, 6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 48(6):1901–1909. doi:10.1021/jm040840e

    Article  CAS  Google Scholar 

  53. Jhoti H (2007) Fragment-based drug discovery using rational design. Ernst Schering Found Symp Proc 3:169–185

    Article  CAS  Google Scholar 

  54. Jhoti H, Leach AR (2007) Structure-based drug discovery. Springer, Dordrecht

    Google Scholar 

  55. Jhoti H, Cleasby A, Verdonk M, Williams G (2007) Fragment-based screening using X-ray crystallography and NMR spectroscopy. Curr Opin Chem Biol 11(5):485–493. doi:10.1016/j.cbpa.2007.07.010

    Article  CAS  Google Scholar 

  56. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425(6956):407–410. doi:10.1038/nature01913

    Article  CAS  Google Scholar 

  57. Kuntz ID, Chen K, Sharp KA, Kollman PA (1999) The maximal affinity of ligands. Proc Natl Acad Sci USA 96(18):9997–10002. doi:10.1073/pnas.96.18.9997

    Article  CAS  Google Scholar 

  58. Leach AR, Hann MM, Burrows JN, Griffen EJ (2006) Fragment screening: an introduction. Mol Biosyst 2(9):430–446. doi:10.1039/b610069b

    Article  CAS  Google Scholar 

  59. Leeson PD, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6(11):881–890. doi:10.1038/nrd2445

    Article  CAS  Google Scholar 

  60. Lepre C (2007) Fragment-based drug discovery using the SHAPES method. Expert Opin Drug Discov 2(12):1555–1566. doi:10.1517/17460441.2.12.1555

    Article  CAS  Google Scholar 

  61. Lewell XQ, Judd DB, Watson SP, Hann MM (1998) RECAP–retrosynthetic combinatorial analysis procedure: a powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry. J Chem Inf Comput Sci 38(3):511–522. doi:10.1021/ci970429i

    CAS  Google Scholar 

  62. Loukine E, Auer J, Bajorath J (2008) Formal concept analysis for the identification of molecular fragment combinations specific for active and highly potent compounds. J Med Chem 51:5342–5348. doi:10.1021/jm800515r

    Article  CAS  Google Scholar 

  63. Makara GM (2007) On sampling of fragment space. J Med Chem 50(14):3214–3221. doi:10.1021/jm0700316

    Article  CAS  Google Scholar 

  64. Mashhoon N, DeMaggio AJ, Tereshko V, Bergmeier SC, Egli M, Hoekstra MF, Kuret J (2000) Crystal structure of a conformation-selective casein kinase-1 inhibitor. J Biol Chem 275(26):20052–20060. doi:10.1074/jbc.M001713200

    Article  CAS  Google Scholar 

  65. Moore WR Jr (2005) Maximizing discovery efficiency with a computationally driven fragment approach. Curr Opin Drug Discov Devel 8(3):355–364

    CAS  Google Scholar 

  66. Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N (2007) Application of fragment screening by X-ray crystallography to beta-secretase. J Med Chem 50(6):1116–1123. doi:10.1021/jm0611962

    Article  CAS  Google Scholar 

  67. Neumann T, Junker HD, Schmidt K, Sekul R (2007) SPR-based fragment screening: advantages and applications. Curr Top Med Chem 7(16):1630–1642. doi:10.2174/156802607782341073

    Article  CAS  Google Scholar 

  68. O’Hare T, Eide CA, Tyner JW, Corbin AS, Wong MJ, Buchanan S, Holme K, Jessen KA, Tang C, Lewis HA et al (2008) SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proc Natl Acad Sci USA 105(14):5507–5512. doi:10.1073/pnas.0800587105

    Article  CAS  Google Scholar 

  69. Oslob JD, Romanowski MJ, Allen DA, Baskaran S, Bui M, Elling RA, Flanagan WM, Fung AD, Hanan EJ, Harris S et al (2008) Discovery of a potent and selective aurora kinase inhibitor. Bioorg Med Chem Lett 18(17):4880–4884. doi:10.1016/j.bmcl.2008.07.073

    Article  CAS  Google Scholar 

  70. Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X et al (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 51(21):6902–6915. doi:10.1021/jm800669s

    Article  CAS  Google Scholar 

  71. Reynolds CH, Tounge BA, Bembenek SD (2008) Ligand binding efficiency: trends, physical basis, and implications. J Med Chem 51(8):2432–2438. doi:10.1021/jm701255b

    Article  CAS  Google Scholar 

  72. Rush TS 3rd, Grant JA, Mosyak L, Nicholls A (2005) A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. J Med Chem 48(5):1489–1495. doi:10.1021/jm040163o

    Article  CAS  Google Scholar 

  73. Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (2008) BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res 6(5):751–759. doi:10.1158/1541-7786.MCR-07-2001

    Article  CAS  Google Scholar 

  74. Schneider G (2002) Trends in virtual combinatorial library design. Curr Med Chem 9(23):2095–2101

    CAS  Google Scholar 

  75. Schneider G, Fechner U (2005) Computer-based de novo design of drug-like molecules. Nat Rev Drug Discov 4(8):649–663. doi:10.1038/nrd1799

    Article  CAS  Google Scholar 

  76. Schuffenhauer A, Ruedisser S, Marzinzik AL, Jahnke W, Blommers M, Selzer P, Jacoby E (2005) Library design for fragment based screening. Curr Top Med Chem 5(8):751–762. doi:10.2174/1568026054637700

    Article  CAS  Google Scholar 

  77. Siegal G, Ab E, Schultz J (2007) Integration of fragment screening and library design. Drug Discov Today 12(23–24):1032–1039. doi:10.1016/j.drudis.2007.08.005

    Article  CAS  Google Scholar 

  78. Siegel MG, Vieth M (2007) Drugs in other drugs: a new look at drugs as fragments. Drug Discov Today 12(1–2):71–79. doi:10.1016/j.drudis.2006.11.011

    Article  CAS  Google Scholar 

  79. Snarey M, Terrett NK, Willett P, Wilton DJ (1997) Comparison of algorithms for dissimilarity-based compound selection. J Mol Graph Model 15(6):372–385. doi:10.1016/S1093-3263(98)00008-4

    Article  CAS  Google Scholar 

  80. Sykora VJ, Leahy DE (2008) Chemical descriptors library (CDL): a generic, open source software library for chemical informatics. J Chem Inf Model 48(10):1931–1942. doi:10.1021/ci800135h

    Article  CAS  Google Scholar 

  81. Taldone T, Sun W, Chiosis G (2008) Discovery and development of heat shock protein 90 inhibitors. Bioorg Med Chem

  82. Taylor JD, Gilbert PJ, Williams MA, Pitt WR, Ladbury JE (2007) Identification of novel fragment compounds targeted against the pY pocket of v-Src SH2 by computational and NMR screening and thermodynamic evaluation. Proteins 67(4):981–990. doi:10.1002/prot.21369

    Article  CAS  Google Scholar 

  83. Verlinde CL, Rudenko G, Hol WG (1992) In search of new lead compounds for trypanosomiasis drug design: a protein structure-based linked-fragment approach. J Comput Aided Mol Des 6(2):131–147. doi:10.1007/BF00129424

    Article  CAS  Google Scholar 

  84. Villar HO, Hansen MR (2007) Computational techniques in fragment based drug discovery. Curr Top Med Chem 7(15):1509–1513. doi:10.2174/156802607782194725

    Article  CAS  Google Scholar 

  85. Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH et al (2002) Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 45(1):219–232. doi:10.1021/jm0103920

    Article  CAS  Google Scholar 

  86. Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H (2007) Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci USA 104(14):5782–5787. doi:10.1073/pnas.0700279104

    Article  CAS  Google Scholar 

  87. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S et al (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49(20):5912–5931. doi:10.1021/jm050362n

    Article  CAS  Google Scholar 

  88. Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE et al (2008) Identification of N-(4-piperidinyl)-4-(2, 6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J Med Chem 51(16):4986–4999. doi:10.1021/jm800382h

    Article  CAS  Google Scholar 

  89. Xu W, Neckers L (2007) Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin Cancer Res 13(6):1625–1629. doi:10.1158/1078-0432.CCR-06-2966

    Article  CAS  Google Scholar 

  90. Zartler ER, Mo H (2007) Practical aspects of NMR-based fragment discovery. Curr Top Med Chem 7(16):1592–1599. doi:10.2174/156802607782341055

    Article  CAS  Google Scholar 

  91. Zartler ER, Shapiro MJ (2008) Fragment-based drug discovery: a practical approach. Wiley, Chichester

    Book  Google Scholar 

  92. Zhou JZ (2008) Structure-directed combinatorial library design. Curr Opin Chem Biol 12(3):379–385. doi:10.1016/j.cbpa.2008.02.007

    Article  CAS  Google Scholar 

  93. Ziegler DS, Kung AL (2008) Therapeutic targeting of apoptosis pathways in cancer. Curr Opin Oncol 20(1):97–103. doi:10.1097/CCO.0b013e3282f310f6

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, OX14 4SA, UK

    Richard Law, Oliver Barker, John J. Barker, Thomas Hesterkamp, Robert Godemann, Ole Andersen, Tara Fryatt, Steve Courtney, Dave Hallett & Mark Whittaker

Authors
  1. Richard Law
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John J. Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Hesterkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Godemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ole Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tara Fryatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steve Courtney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dave Hallett
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark Whittaker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Law.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Law, R., Barker, O., Barker, J.J. et al. The multiple roles of computational chemistry in fragment-based drug design. J Comput Aided Mol Des 23, 459–473 (2009). https://doi.org/10.1007/s10822-009-9284-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-009-9284-1

Keywords

Search

Navigation