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Introduction to Fragment-Based Drug Discovery

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Fragment-Based Drug Discovery and X-Ray Crystallography

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 317))

Abstract

Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement.

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References

  1. Adams D (1980) The hitchhiker’s guide to the galaxy, 1st American edn. Harmony Books, New York

    Google Scholar 

  2. Bohacek RS, McMartin C, Guida WC (1996) The art and practice of structure-based drug design: a molecular modeling perspective. Med Res Rev 16:3–50

    CAS  Google Scholar 

  3. Hann MM, Oprea TI (2004) Pursuing the leadlikeness concept in pharmaceutical research. Curr Opin Chem Biol 8:255–263

    CAS  Google Scholar 

  4. Keseru GM, Makara GM (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov 8:203–212

    Google Scholar 

  5. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  7. Fink T, Reymond JL (2007) Virtual exploration of the chemical universe up to 11 atoms of C, N, O, F: assembly of 26.4 million structures (110.9 million stereoisomers) and analysis for new ring systems, stereochemistry, physicochemical properties, compound classes, and drug discovery. J Chem Inf Model 47:342–353

    CAS  Google Scholar 

  8. Jencks WP (1981) On the attribution and additivity of binding energies. Proc Nat Acad Sci USA 78:4046–4050

    CAS  Google Scholar 

  9. Shuker SB, Hajduk PJ, Meadows RP et al (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274:1531–1534

    CAS  Google Scholar 

  10. Chung S, Parker JB, Bianchet M et al (2009) Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nat Chem Biol 5:407–413

    CAS  Google Scholar 

  11. Huth JR, Park C, Petros AM et al (2007) Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies. Chem Biol Drug Des 70:1–12

    CAS  Google Scholar 

  12. Whittaker M (2009) Picking up the pieces with FBDD or FADD: invest early for future success. Drug Discov Today 14:623–624

    Google Scholar 

  13. 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 41:856–864

    CAS  Google Scholar 

  14. Rishton GM (2003) Nonleadlikeness and leadlikeness in biochemical screening. Drug Discov Today 8:86–96

    CAS  Google Scholar 

  15. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53:2719–2740

    CAS  Google Scholar 

  16. Baell JB (2010) Observations on screening-based research and some concerning trends in the literature. Future Med Chem 2:1529–1546

    CAS  Google Scholar 

  17. Guertin KR, Setti L, Qi L et al (2003) Identification of a novel class of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents with protein tyrosine phosphatase inhibitory activity. Bioorg Med Chem Lett 13:2895–2898

    CAS  Google Scholar 

  18. Tjernberg A, Hallen D, Schultz J et al (2004) Mechanism of action of pyridazine analogues on protein tyrosine phosphatase 1B (PTP1B). Bioorg Med Chem Lett 14:891–895

    CAS  Google Scholar 

  19. Yi F, Regan L (2008) A novel class of small molecule inhibitors of Hsp90. ACS Chem Biol 3:645–654

    CAS  Google Scholar 

  20. Lor LA, Schneck J, McNulty DE et al (2007) A simple assay for detection of small-molecule redox activity. J Biomol Screen 12:881–890

    CAS  Google Scholar 

  21. Johnston PA, Soares KM, Shinde SN et al (2008) Development of a 384-well colorimetric assay to quantify hydrogen peroxide generated by the redox cycling of compounds in the presence of reducing agents. Assay Drug Dev Technol 6:505–518

    CAS  Google Scholar 

  22. Soares KM, Blackmon N, Shun TY et al (2010) Profiling the NIH small molecule repository for compounds that generate H2O2 by redox cycling in reducing environments. Assay Drug Dev Technol 8:152–174

    CAS  Google Scholar 

  23. McGovern SL, Caselli E, Grigorieff N et al (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712–1722

    CAS  Google Scholar 

  24. Seidler J, McGovern SL, Doman TN et al (2003) Identification and prediction of promiscuous aggregating inhibitors among known drugs. J Med Chem 46:4477–4486

    CAS  Google Scholar 

  25. Babaoglu K, Simeonov A, Irwin JJ et al (2008) Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase. J Med Chem 51:2502–2511

    CAS  Google Scholar 

  26. Ferreira RS, Bryant C, Ang KK et al (2009) Divergent modes of enzyme inhibition in a homologous structure-activity series. J Med Chem 52:5005–5008

    CAS  Google Scholar 

  27. Feng BY, Shoichet BK (2006) A detergent-based assay for the detection of promiscuous inhibitors. Nat Protoc 1:550–553

    CAS  Google Scholar 

  28. Shoichet BK (2006) Screening in a spirit haunted world. Drug Discov Today 11:607–615

    CAS  Google Scholar 

  29. Pellecchia M, Bertini I, Cowburn D et al (2008) Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov 7:738–745

    CAS  Google Scholar 

  30. Mayer M, Meyer B (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew Chem Int Ed Engl 38:1784–1788

    CAS  Google Scholar 

  31. Becattini B, Culmsee C, Leone M et al (2006) Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid. Proc Natl Acad Sci USA 103:12602–12606

    CAS  Google Scholar 

  32. Becattini B, Pellecchia M (2006) SAR by ILOEs: an NMR-based approach to reverse chemical genetics. Chemistry 12:2658–2662

    CAS  Google Scholar 

  33. Sledz P, Silvestre HL, Hung AW et al (2010) Optimization of the interligand Overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase. J Am Chem Soc 132:4544–4545

    CAS  Google Scholar 

  34. Vanwetswinkel S, Heetebrij RJ, van Duynhoven J et al (2005) TINS, target immobilized NMR screening: an efficient and sensitive method for ligand discovery. Chem Biol 12:207–216

    CAS  Google Scholar 

  35. Fruh V, Zhou Y, Chen D et al (2010) Application of fragment-based drug discovery to membrane proteins: identification of ligands of the integral membrane enzyme DsbB. Chem Biol 17:881–891

    Google Scholar 

  36. Pellecchia M, Becattini B, Crowell KJ et al (2004) NMR-based techniques in the hit identification and optimisation processes. Expert Opin Ther Targets 8:597–611

    CAS  Google Scholar 

  37. Zartler ER, Shapiro MJ (2006) Protein NMR-based screening in drug discovery. Curr Pharm Des 12:3963–3972

    CAS  Google Scholar 

  38. Sem DS (2006) NMR-guided fragment assembly. In: Jahnke W, Erlanson DA (eds) Fragment-based approaches in drug discovery. Wiley-VCH, Weinheim, Germany

    Google Scholar 

  39. Hajduk PJ, Huth JR, Sun C (2006) SAR by NMR: an analysis of potency gains realized through fragment-linking and fragment-elaboration strategies for lead generation. In: Jahnke W, Erlanson DA (eds) Fragment-based approaches in drug discovery. Wiley-VCH, Weinheim

    Google Scholar 

  40. Zartler ER, Mo H (2007) Practical aspects of NMR-based fragment discovery. Curr Top Med Chem 7:1592–1599

    CAS  Google Scholar 

  41. Hubbard RE, Davis B, Chen I et al (2007) The SeeDs approach: integrating fragments into drug discovery. Curr Top Med Chem 7:1568–1581

    CAS  Google Scholar 

  42. Dalvit C (2009) NMR methods in fragment screening: theory and a comparison with other biophysical techniques. Drug Discov Today 14:1051–1057

    CAS  Google Scholar 

  43. Jhoti H, Cleasby A, Verdonk M et al (2007) Fragment-based screening using X-ray crystallography and NMR spectroscopy. Curr Opin Chem Biol 11:485–493

    CAS  Google Scholar 

  44. Kobayashi M, Retra K, Figaroa F et al (2010) Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification. J Biomol Screen 15:978–989

    CAS  Google Scholar 

  45. Gozalbes R, Carbajo RJ, Pineda-Lucena A (2010) Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery. Curr Med Chem 17:1769–1794

    CAS  Google Scholar 

  46. Wyss DF, Wang Y-S, Eaton HL, Strickland C, Voigt JH, Zhu Z, Stamford AW (2011) Combining NMR and X-ray crystallography in fragment-based drug discovery: discovery of highly potent and selective BACE-1 inhibitors. Top Curr Chem. doi:10.1007/128_2011_183

    Google Scholar 

  47. Bauman JD, Patel D, Arnold E (2011) Fragment screening and HIV therapeutics. Top Curr Chem. doi:10.1007/128_2011_232

    Google Scholar 

  48. Davies TG, Tickle IJ (2011) Fragment screening using X-ray crystallography. Top Curr Chem. doi:10.1007/128_2011_179

    Google Scholar 

  49. 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_2011_225

    Google Scholar 

  50. Davis AM, St-Gallay SA, Kleywegt GJ (2008) Limitations and lessons in the use of X-ray structural information in drug design. Drug Discov Today 13:831–841

    CAS  Google Scholar 

  51. Sondergaard CR, Garrett AE, Carstensen T et al (2009) Structural artifacts in protein-ligand X-ray structures: implications for the development of docking scoring functions. J Med Chem 52:5673–5684

    CAS  Google Scholar 

  52. Blaney J, Nienaber V, Burley SK (2006) Fragment-based lead discovery and optimization using X-ray crystallography, computational chemistry, and high-throughput organic synthesis. In: Jahnke W, Erlanson DA (eds) Fragment-based approaches in drug discovery. Wiley-VCH, Weinheim

    Google Scholar 

  53. Murray CW, Blundell TL (2010) Structural biology in fragment-based drug design. Curr Opin Struct Biol 20:497–507

    CAS  Google Scholar 

  54. Rich RL, Myszka DG (2010) Grading the commercial optical biosensor literature-class of 2008: ‘The mighty binders’. J Mol Recognit 23:1–64

    CAS  Google Scholar 

  55. Perspicace S, Banner D, Benz J et al (2009) Fragment-based screening using surface plasmon resonance technology. J Biomol Screen 14:337–349

    CAS  Google Scholar 

  56. Proll F, Fechner P, Proll G (2009) Direct optical detection in fragment-based screening. Anal Bioanal Chem 393:1557–1562

    Google Scholar 

  57. Navratilova I, Hopkins AL (2010) Fragment screening by surface plasmon resonance. ACS Med Chem Lett 1:44–48

    CAS  Google Scholar 

  58. Rich RL, Myszka DG (2010) Kinetic analysis and fragment screening with Fujifilm AP-3000. Anal Biochem 402:170–178

    CAS  Google Scholar 

  59. Kreatsoulas C, Narayan K (2010) Algorithms for the automated selection of fragment-like molecules using single-point surface plasmon resonance measurements. Anal Biochem 402:179–184

    CAS  Google Scholar 

  60. Neumann T, Junker HD, Schmidt K et al (2007) SPR-based fragment screening: advantages and applications. Curr Top Med Chem 7:1630–1642

    CAS  Google Scholar 

  61. Concepcion J, Witte K, Wartchow C et al (2009) Label-free detection of biomolecular interactions using biolayer interferometry for kinetic characterization. Comb Chem High Throughput Screen 12:791–800

    CAS  Google Scholar 

  62. Ladbury JE, Klebe G, Freire E (2010) Adding calorimetric data to decision making in lead discovery: a hot tip. Nat Rev Drug Discov 9:23–27

    CAS  Google Scholar 

  63. Scott AD, Phillips C, Alex A et al (2009) Thermodynamic optimisation in drug discovery: a case study using carbonic anhydrase inhibitors. ChemMedChem 4:1985–1989

    CAS  Google Scholar 

  64. Erlanson DA, Wells JA, Braisted AC (2004) Tethering: fragment-based drug discovery. Annu Rev Biophys Biomol Struct 33:199–223

    CAS  Google Scholar 

  65. Hannah V, Atmanene C, Zeyer D et al (2010) Native MS: an ‘ESI’ way to support structure-and fragment-based drug discovery. Future Med Chem 2:35–49

    CAS  Google Scholar 

  66. Barker J, Courtney S, Hesterkamp T et al (2006) Fragment screening by biochemical assay. Expert Opin Drug Discovery 1:225–236

    CAS  Google Scholar 

  67. Slack M, Winkler D, Kramer J et al (2009) A multiplexed approach to hit finding. Curr Opin Drug Discov Devel 12:351–357

    CAS  Google Scholar 

  68. Godemann R, Madden J, Kramer J et al (2009) Fragment-based discovery of BACE1 inhibitors using functional assays. Biochemistry 48:10743–10751

    CAS  Google Scholar 

  69. Barker JJ, Barker O, Boggio R et al (2009) Fragment-based identification of Hsp90 inhibitors. ChemMedChem 4:963–966

    CAS  Google Scholar 

  70. Tsai J, Lee JT, Wang W et al (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105:3041–3046

    CAS  Google Scholar 

  71. Artis DR, Lin JJ, Zhang C et al (2009) Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci USA 106:262–267

    CAS  Google Scholar 

  72. Caflisch A, Miranker A, Karplus M (1993) Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase. J Med Chem 36:2142–2167

    CAS  Google Scholar 

  73. Teotico DG, Babaoglu K, Rocklin GJ et al (2009) Docking for fragment inhibitors of AmpC beta-lactamase. Proc Natl Acad Sci USA 106:7455–7460

    CAS  Google Scholar 

  74. Zoete V, Grosdidier A, Michielin O (2009) Docking, virtual high throughput screening and in silico fragment-based drug design. J Cell Mol Med 13:238–248

    CAS  Google Scholar 

  75. Law R, Barker O, Barker JJ et al (2009) The multiple roles of computational chemistry in fragment-based drug design. J Comput Aided Mol Des 23:459–473

    CAS  Google Scholar 

  76. Albert JS, Blomberg N, Breeze AL 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 7:1600–1629

    CAS  Google Scholar 

  77. Congreve M, Carr R, Murray C et al (2003) A ‘rule of three’ for fragment-based lead discovery? Drug Discov Today 8:876–877

    Google Scholar 

  78. Hopkins AL, Groom CR, Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9:430–431

    Google Scholar 

  79. Hajduk PJ (2006) Fragment-based drug design: how big is too big? J Med Chem 49:6972–6976

    CAS  Google Scholar 

  80. Kuntz ID, Chen K, Sharp KA et al (1999) The maximal affinity of ligands. Proc Natl Acad Sci USA 96:9997–10002

    CAS  Google Scholar 

  81. Abad-Zapatero C, Metz G (2005) Ligand efficiency indices as guideposts for drug discovery. Drug Discov Today 10:464–469

    Google Scholar 

  82. Bembenek SD, Tounge BA, Reynolds CH (2009) Ligand efficiency and fragment-based drug discovery. Drug Discov Today 14:278–283

    CAS  Google Scholar 

  83. Orita M, Ohno K, Niimi T (2009) Two ‘golden ratio’ indices in fragment-based drug discovery. Drug Discov Today 14:321–328

    CAS  Google Scholar 

  84. Erlanson DA, McDowell RS, O’Brien T (2004) Fragment-based drug discovery. J Med Chem 47:3463–3482

    CAS  Google Scholar 

  85. Rees DC, Congreve M, Murray CW et al (2004) Fragment-based lead discovery. Nat Rev Drug Discov 3:660–672

    CAS  Google Scholar 

  86. Jahnke W, Erlanson DA (eds) (2006) Fragment-based approaches in drug discovery. Methods and principles in medicinal chemistry, vol 34. Wiley-VCH, Weinheim, Germany

    Google Scholar 

  87. Zartler E, Shapiro M (eds) (2008) Fragment-based drug discovery: a practical approach. Wiley, Hoboken

    Google Scholar 

  88. Erlanson DA (2006) Fragment-based lead discovery: A chemical update. Curr Opin Biotechnol 17:643–652

    CAS  Google Scholar 

  89. Leach AR, Hann MM, Burrows JN et al (2006) Fragment screening: an introduction. Mol Biosyst 2:430–446

    Google Scholar 

  90. Ciulli A, Abell C (2007) Fragment-based approaches to enzyme inhibition. Curr Opin Biotechnol 18:489–496

    CAS  Google Scholar 

  91. Fattori D, Squarcia A, Bartoli S (2008) Fragment-based approach to drug lead discovery: overview and advances in various techniques. Drugs R D 9:217–227

    CAS  Google Scholar 

  92. Congreve M, Chessari G, Tisi D et al (2008) Recent developments in fragment-based drug discovery. J Med Chem 51:3661–3680

    CAS  Google Scholar 

  93. Murray CW, Rees DC (2009) The rise of fragment-based drug discovery. Nat Chem 1:187–192

    CAS  Google Scholar 

  94. Schulz MN, Hubbard RE (2009) Recent progress in fragment-based lead discovery. Curr Opin Pharmacol 9:615–621

    CAS  Google Scholar 

  95. de Kloe GE, Bailey D, Leurs R et al (2009) Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discov Today 14:630–646

    Google Scholar 

  96. Coyne AG, Scott DE, Abell C (2010) Drugging challenging targets using fragment-based approaches. Curr Opin Chem Biol 14:299–307

    CAS  Google Scholar 

  97. Chessari G, Woodhead AJ (2009) From fragment to clinical candidate–a historical perspective. Drug Discov Today 14:668–675

    CAS  Google Scholar 

  98. Erlanson DA (2010) Fragments in the clinic: 2010 edition. In: Practical fragments. http://practicalfragments.blogspot.com/2010/09/fragments-in-clinic-2010-edition.html. Accessed 23 Dec 2010

  99. Li R, Stafford JA (eds) (2009) Kinase inhibitor drugs. Wiley series in drug discovery and development. Wiley, Hoboken

    Google Scholar 

  100. Akritopoulou-Zanze I, Hajduk PJ (2009) Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors. Drug Discov Today 14:291–297

    CAS  Google Scholar 

  101. Wyatt PG, Woodhead AJ, Berdini V 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 51:4986–4999

    CAS  Google Scholar 

  102. Howard S, Berdini V, Boulstridge JA 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 52:379–388

    CAS  Google Scholar 

  103. Erlanson D, Braisted A, Raphael D et al (2000) Site-directed ligand discovery. Proc Natl Acad Sci USA 97:9367–9372

    CAS  Google Scholar 

  104. Mpamhanga CP, Spinks D, Tulloch LB et al (2009) One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J Med Chem 52:4454–4465

    CAS  Google Scholar 

  105. Bollag G, Hirth P, Tsai J et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599

    CAS  Google Scholar 

  106. Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819

    CAS  Google Scholar 

  107. Brough PA, Aherne W, Barril X et al (2008) 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51:196–218

    CAS  Google Scholar 

  108. Brough PA, Barril X, Borgognoni J et al (2009) Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52:4794–4809

    CAS  Google Scholar 

  109. Roughley S, Wright L, Brough P, Massey A, Hubbard RE (2011) Hsp90 inhibitors and drugs from fragment and virtual screening. Top Curr Chem. doi:10.1007/128_181

    Google Scholar 

  110. Murray CW, Carr MG, Callaghan O et al (2010) Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem 53:5942–5955

    CAS  Google Scholar 

  111. Woodhead AJ, Angove H, Carr MG et al (2010) Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem 53:5956–5969

    CAS  Google Scholar 

  112. Hajduk PJ, Sheppard G, Nettesheim DG et al (1997) Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 119:5818–5827

    CAS  Google Scholar 

  113. Hajduk PJ, Shuker SB, Nettesheim DG et al (2002) NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. J Med Chem 45:5628–5639

    CAS  Google Scholar 

  114. Wada CK (2004) The evolution of the matrix metalloproteinase inhibitor drug discovery program at Abbott Laboratories. Curr Top Med Chem 4:1255–1267

    CAS  Google Scholar 

  115. Oltersdorf T, Elmore SW, Shoemaker AR et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681

    CAS  Google Scholar 

  116. Petros AM, Dinges J, Augeri DJ et al (2006) Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem 49:656–663

    CAS  Google Scholar 

  117. Wendt MD, Shen W, Kunzer A et al (2006) Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J Med Chem 49:1165–1181

    CAS  Google Scholar 

  118. Bruncko M, Oost TK, Belli BA et al (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50:641–662

    CAS  Google Scholar 

  119. Park CM, Bruncko M, Adickes J et al (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 51:6902–6915

    CAS  Google Scholar 

  120. Davies DR, Mamat B, Magnusson OT et al (2009) Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J Med Chem 52:4694–4715

    CAS  Google Scholar 

  121. Penning TD, Chandrakumar NS, Chen BB et al (2000) Structure-activity relationship studies on 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. J Med Chem 43:721–735

    CAS  Google Scholar 

  122. Sandanayaka V, Mamat B, Mishra RK et al (2010) Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. J Med Chem 53:573–585

    CAS  Google Scholar 

  123. Nienaber VL, Richardson PL, Klighofer V et al (2000) Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat Biotechnol 18:1105–1108

    CAS  Google Scholar 

  124. Sun C (2010) Targeting the intractable. Oral presentation at: Fragment-based lead discovery conference 2010, Philadelphia, 10–13 October 2010

    Google Scholar 

  125. Haydon DJ, Stokes NR, Ure R et al (2008) An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321:1673–1675

    CAS  Google Scholar 

  126. Czaplewski LG, Collins I, Boyd EA et al (2009) Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorg Med Chem Lett 19:524–527

    CAS  Google Scholar 

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Acknowledgment

I would like to thank Monya Baker for a careful reading of the manuscript.

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  1. Carmot Therapeutics, Inc., 409 Illinois Street, San Francisco, CA, 94158, USA

    Daniel A. Erlanson

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Correspondence to Daniel A. Erlanson .

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  1. Astex Pharmaceuticals, Milton Road, Cambridge, CB4 0QA, United Kingdom

    Thomas G. Davies

  2. , Department of Biochemistry, University of Cambridge, Tennis Court Road 80, Cambridge, CB2 1GA, United Kingdom

    Marko Hyvönen

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Erlanson, D.A. (2011). Introduction to Fragment-Based Drug Discovery. In: Davies, T., Hyvönen, M. (eds) Fragment-Based Drug Discovery and X-Ray Crystallography. Topics in Current Chemistry, vol 317. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2011_180

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