Fragment-based drug design (FBDD)

Authors

  • A. P. Kryshchyshyn Lviv National Medical University named after Danylo Halytsky, Ukraine

DOI:

https://doi.org/10.24959/ophcj.17.913

Keywords:

fragment-based drug design FBDD, molecular fragment, ligand efficiency

Abstract

Fragment-based drug design (FBDD) is one of the modern techniques used for developing new drugs, and an alternative to the widely used high throughput screening. The main methodological approaches of FBDD, as well as the methods of optimization for the identified “fragments“ when transferring them to the drug-like molecules have been described. The basic principles of the biophysical methods for analysis of the fragment – bio-target complexes and their application have been shown. Advantages and disadvantages of such methods as fluorescence-based thermal shift, NMR-spectroscopy, mass spectrometry, surface plasmon resonance are discussed. The most informative and efficient tool for the complex screening is X-ray crystallography. The main approaches to development of the pharmacologically active molecules based on the identified fragments, namely the methods of “fragment merging”, “fragment linking” and “fragment growing”, are given. The prospects and importance of the given method has been confirmed by the specific examples of drug candidates and the antitumor drug Vemurafenib approved and developed using FBDD.

Downloads

Download data is not yet available.

References

  1. Keseru, G. M. The influence of lead discovery strategies on the properties of drug candidates / G. M. Keseru, G. M. Makara // Nature reviews Drug Discovery. – 2009. – Vol. 8, Issue 3. – P. 203–212. doi : 10.1038/nrd2796.
  2. Hajduk, P. J. A decade of fragment–based drug design: strategic advances and lessons learned / P. J. Hajduk, J. Greer // Nature reviews Drug discovery. – 2007. – Vol. 6, Issue 3. – P. 211–219. doi : 10.1038/nrd2220.
  3. Erlanson, D. A. Introduction to Fragment–Based Drug Discovery. In Fragment–based drug discovery and X–ray crystallography (Topics in current chemistry 317) / D. A. Erlanson // SpringerBerlinHeidelberg. – 2014. – Vol. 225. – P. 1–32. doi : 10.1007/128_2011_180.
  4. Fink, T. 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 / T. Fink, J. L. Reymond // Journal of chemical information and modeling. – 2007. – Vol. 47, Issue 2. – P. 342–353. doi : 10.1021/ci600423u.
  5. Fragment–based approaches in drug discovery and chemical biology / D. E. Scott, A. G. Coyne, S. A. Hudson, C. Abell // Biochemistry. – 2012. – Vol. 51, Issue 25. – P. 4990–5003. doi : 10.1021/bi3005126.
  6. Jencks, W. P. On the attribution and additivity of binding energies / W. P. Jencks // Proceedings of the National Academy of Sciences. – 1981. – Vol. 78, Issue 7. – P. 4046–4050. doi : 10.1073/pnas.78.7.4046.
  7. Discovering high–affinity ligands for proteins: SAR by NMR / S. B. Shuker, P. J. Hajduk, R. P. Meadows, S. W. Fesik // Science. – 1996. – Vol. 274, Issue 5292. – P. 1531–1534. doi : 10.1126/science.274.5292.1531.
  8. Impact of linker strain and flexibility in the design of a fragment–based inhibitor / S. Chung, J. B. Parker, M. Bianchet et al. // Nature chemical biology. – 2009. –Vol. 5, Issue 6. – P. 407–413. doi : 10.1038/nchembio.163.
  9. Discovery and design of novel HSP90 inhibitors using multiple fragment–based design strategies / J. R. Huth, C. Park, A. M. Petros et al. // Chemical biology & drug design. – 2007. – Vol. 70, Issue 1. – P. 1–12. doi : 10.1111/j.1747–0285.2007.00535.x.
  10. Hann, M. M. Molecular complexity and its impact on the probability of finding leads for drug discovery / M. M. Hann, A. R. Leach, G. Harper // Journal of chemical information and computer sciences. – 2001. – Vol. 41, Issue 3. – P. 856–864. doi : 10.1021/ci000403i.
  11. Rishton, G. M. Nonleadlikeness and leadlikeness in biochemical screening / G. M. Rishton // Drug Discovery Today. – 2003. – Vol. 8, Issue 2. – P. 86–96. doi : 10.1016/s1359644602025722.
  12. Baell, J. B. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays / J. B. Baell, G. A. Holloway // Journal of Medicinal Chemistry. – 2010. – Vol. 53, Issue 7. – P. 2719–2740. doi : 10.1021/jm901137j.
  13. 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 / K. R. Guertin, L. Setti, L. Qi et al. // Bioorganic & Medicinal Chemistry Letters. – 2003. – Vol. 13, Issue 46. – P. 2895–2898. doi : 10.1002/chin.200346171.
  14. Mechanism of action of pyridazine analogues on protein tyrosine phosphatase 1B (PTP1B) / A. Tjernberg, D. Hallen, J. Schultz et al. // Bioorganic & Medicinal Chemistry Letters. – 2004. – Vol. 14, Issue 4. – P. 891–895. doi : 10.1016/j.bmcl.2003.12.014.
  15. Yi, F. A novel class of small molecule inhibitors of Hsp90 / F. Yi, L. Regan // ACS Chemical Biology. – 2008. – Vol. 3, Issue 10. – P. 645–654. doi : 10.1021/cb800162x.
  16. A simple assay for detection of small–molecule redox activity / L. A. Lor, J. Schneck, D. E. McNulty et al. // Journal of Biomolecular Screening. – 2007. – Vol. 12, Issue 6. – P. 881–890. doi : 10.1177/1087057107304113.
  17. Profiling the NIH small molecule repository for compounds that generate H2O2 by redox cycling in reducing environments / K. M. Soares, N. Blackmon, T. Y. Shun et al. // Assay and Drug Development Technologies. – 2010. – Vol. 8, Issue 2. – P. 152–174. doi : 10.1089/adt.2009.0247.
  18. A common mechanism underlying promiscuous inhibitors from virtual and high–throughput screening / S. L. McGovern, E. Caselli, N. Grigorieff et al. // Journal of Medicinal Chemistry. – 2002. – Vol. 45, Issue 8. – P.1712–1722. doi : 10.1021/jm010533y.
  19. Identification and prediction of promiscuous aggregating inhibitors among known drugs / J. Seidler, S. L. McGovern, T. N. Doman et al. // Journal of Medicinal Chemistry. – 2003. – Vol. 46, Issue 21. – P. 4477–4486. doi : 10.1021/jm030191r.
  20. Comprehensive mechanistic analysis of hits from high–throughput and docking screens against beta–lactamase / K. Babaoglu, A. Simeonov, J. J. Irwin et al. // Journal of Medicinal Chemistry. – 2008. – Vol. 51, Issue 8. – P. 2502–2511. doi : 10.1021/jm701500e.
  21. Divergent modes of enzyme inhibition in a homologous structure–activity series / R. S. Ferreira, C. Bryant, K. K. Ang et al. // Journal of Medicinal Chemistry. – 2009. – Vol. 52, Issue 16. – P. 5005–5008. doi : 10.1021/jm9009229.
  22. Feng, B. Y. A detergent–based assay for the detection of promiscuous inhibitors / B. Y. Feng, B. K. Shoichet // Nature Protocols. – 2006. – Vol. 1, Issue 2. – P. 550–553. doi : 10.1038/nprot.2006.77.
  23. Shoichet, B. K. Screening in a spirit haunted world / B. K. Shoichet // Drug Discovery Today. – 2006. – Vol. 11, Issue 13–14. – P. 607–615. doi : 10.1016/j.drudis.2006.05.014.
  24. Hopkins, A. L. Ligand efficiency: a useful metric for lead selection /A. L. Hopkins, C. R. Groom, A. Alex // Drug Discovery Today. – 2004. – Vol. 9, Issue 10. – P. 430–431. doi : 10.1016/s1359–6446(04)03069–7.
  25. The maximal affinity of ligands / I. D. Kuntz, K. Chen, K. A. Sharp, P. A. Kollman // Proceedings of theNationalAcademyof Sciences. – 1999. – Vol. 96, Issue 18. – P. 9997–10002. doi : 10.1073/pnas.96.18.9997.
  26. A ‘rule of three’ for fragment–based lead discovery? / M. Congreve, R. Carr, C. Murray, H. Jhoti // Drug Discovery Today. – 2003. – Vol. 8, Issue 19. – P. 876–877. doi : 10.1016/s1359–6446(03)02831–9.
  27. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings / C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney // Advanced Drug Delivery Reviews. – 2012. – Vol. 64. – P. 4–17. doi : 10.1016/j.addr.2012.09.019.
  28. Hann, M. M. Molecular complexity and its impact on the probability of finding leads for drug discovery / M. M. Hann, A. R. Leach, G. Harper // Journal of Chemical Information and Computer Sciences. – 2001. – Vol. 41, Issue 3. – P. 856–864. doi : 10.1021/ci000403i.
  29. Is there a difference between leads and drugs? A historical perspective / T. I. Oprea, A. M. Davis, S. J. Teague, P. D. Leeson // Journal of Chemical Information and Computer Sciences. – 2001. – Vol. 41, Issue 5. – P. 1308–1315. doi : 10.1021/ci010366a.
  30. The design of leadlike combinatorial libraries / S. J. Teague, A. M. Davis, P. D. Leeson, T. Oprea // Angewandte Chemie International Edition. – 1999. – Vol. 38, Issue 24. – P. 3743–3748. doi : 10.1002/(sici)1521–3773(19991216)38:24<3743::aid–anie3743>3.3.co;2–l.
  31. Fragment–based leads discovery: leads by design / R. A. E. Carr, M. Congreve,Ch. W. Murray, D. C. Rees // Drug Discovery Today. – 2005. – Vol.10, Issue 14. – P. 987–992. doi : 10.1016/s1359–6446(05)03511–7.
  32. Kranz, J. Protein thermal shifts to identify low molecular weight fragments / J. Kranz, Schalk –Hihi // Methods Enzymol. – 2011. – Vol. 493. – P. 277–298. doi : 10.1016/b978–0–12–381274–2.00011–x.
  33. Toward the rational design of p53–stabilizing drugs: probing the surface of the oncogenic Y220C mutant /N. Basse, J. L. Kaar, G. Settanni et al. // Chemistry & Biology. – 2010. – Vol. 17, Issue 1. – P. 46–56. doi : 10.1016/j.chembiol.2009.12.011.
  34. Combining hit 15 identification strategies: Fragment–based and in silico approaches to orally active 2–aminothieno[2,3–d]pyrimidine inhibitors of the Hsp90 molecular chaperone / P. A. Brough, X. Barril, J. Borgognoni et al. // Journal of Medicinal Chemistry. – 2009. – Vol. 52, Issue 15. – P. 4794−4809. doi : 10.1021/jm900357y.
  35. Klages, J. NMR–based screening: A powerful tool in fragment–based drug discovery / J. Klages, M. Coles, H. Kessler // Analyst. – 2007. – Vol. 132, Issue 7. – P. 693−705. doi : 10.1039/b709658p.
  36. Hajduk, P. J. One dimensional relaxation– and diffusion–edited NMR m ethods for screening compounds that bind to macromolecules / P. J. Hajduk, E. T. Olejniczak, S. W. Fesik // Journal of the American Chemical Society. – 1997. – Vol. 119, Issue 50. – P. 12257−12261. doi :10.1021/ja9715962.
  37. Mayer, M. Characterization of ligand binding by saturation transfer difference NMR spectroscopy / M. Mayer, B. Meyer // Angewandte Chemie International Edition. – 1999. – Vol. 38, Issue 12. – P.1784–1788. doi : 10.1002/(sici)1521–3773(19990614)38:12<1784::aid–anie1784>3.3.co;2–h.
  38. Taldone, T. Discovery and development of heat shock protein 90 inhibitors / T. Taldone, W. Sun, G. Chiosis // Bioorganic & Medicinal Chemistry. – 2009. – Vol. 17, Issue 6. – P. 2225−2235. doi : 10.1016/j.bmc.2008.10.087.
  39. Electron density guided fragment–based lead discovery of ketohexokinase inhibitors / A. C. Gibbs, M. C. Abad, X. Zhang et al. // Journal of Medicinal Chemistry. – 2010. – Vol. 53, Issue 22. – 7979−7991. doi : 10.1021/jm100677s.
  40. Davies, T. G. Fragment–Based Drug Discovery and X–Ray Crystallography / T. G. Davies, M. Hyvönen. –Germany: SpringerHeidelberg, 2012. – 225. doi : 10.1007/978–3–642–27540–1.
  41. Blundell, T. L. High–throughput crystallography for lead discovery in drug design / T. L. Blundell, H. Jhoti, C. Abell // Nature Reviews Drug Discovery. – 2002. – Vol. 1, Issue 1. – P. 45−54. doi : 10.1038/nrd706.
  42. 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 / P. G. Wyatt, A. J. Woodhead, V. Berdini et al. // Journal of Medicinal Chemistry. – 2008. – Vol. 51. – P. 4986−4999. doi : 10.2210/pdb2vto/pdb.
  43. Hofstadler, S. A. Applications of ESI–MS in drug discovery: Interrogation of noncovalent complexes / S. A. Hofstadler, K. A. Sannes–Lowery // Nature Reviews Drug Discovery. – 2006. – Vol. 5, Issue 7. – P. 585−595. doi : 10.1038/nrd2083.
  44. Navratilova, I. Fragment screening by surface plasmon resonance / I. Navratilova, A. L. Hopkins // ACS Medicinal Chemistry Letters. – 2010. – Vol. 1, Issue 1. – P. 44−48. doi : 10.1021/ml900002k.
  45. Optimization of the interligand Overhauser effect for fragment linking: Application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase / P. Sledz, H. L. Silvestre, A. W. Hung et al. // Journal of the American Chemical Society. – 2010. – Vol. 132, Issue 13. – P. 4544−4545. doi : 10.1021/ja100595u.
  46. SERAPhiC: A benchmark for in silico fragment–based drug design / A. D. Favia, G. Bottegoni,I.Nobeli et al. // Journal of Chemical Information and Modeling. – 2011. – Vol. 51, Issue 11. – P. 2882−2896. doi : 10.1021/ci2003363.
  47. Discovery of a potent inhibitor of the antiapoptotic protein Bcl–x(L) from NMR and parallel synthesis / A. M. Petros, J. Dinges, D. J. Augeri et al. // Journal of Medicinal Chemistry. – 2006. – Vol. 49, Issue 2. – P. 656−663. doi : 10.1021/jm0507532.
  48. Fragment–based screening by X–ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N–methyltransferase) inhibitors / N. Drinkwater, H. Vu, K. M. Lovell et al. // Biochemical Journal. – 2010. – Vol. 431, Issue 1. – P. 51−61. doi : 10.1042/bj20100651.
  49. Fragment growing induces conformational changes in acetylcholinebinding protein: A structural and thermodynamic analysis / E. Edink, P. Rucktooa, K. Retra et al. // Journal of the American Chemical Society. – 2011. – Vol. 133. – P. 5363−5371. doi : 10.1021/ja110571r.
  50. 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 / P. A. Brough, X. Barril, J. Borgognoni et al. // Journal of Medicinal Chemistry. – 2009. – Vol. 52, Issue 12. – P. 4794−4809. doi : 10.1021/jm900357y.
  51. Fragment based discovery of a novel and selective PI3 kinase inhibitor / S. J. Hughes, D. S. Millan, I. C. Kilty et al. // Bioorganic & Medicinal Chemistry Letters. – 2011. – Vol. 21, Issue 21. – P. 6586–6590. doi : 10.1016/j.bmcl.2011.07.117.
  52. Murray, C. W. The consequences of translational and rotational entropy lost by small molecules on binding to proteins / C. W. Murray, M. L. Verdonk // Journal of Computer–Aided Molecular Design. – 2002. – Vol. 16. – P. 741−753. doi : 10.1023/A:1022446720849.
  53. Molecular properties that influence the oral bioavailability of drug candidates / D. F. Veber, S. R. Johnson, H. Y. Cheng et al. // Journal of Medicinal Chemistry. – 2002. – Vol. 45, Issue 12. – P. 2615−2623. doi : 10.1021/jm020017n.
  54. Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors / N. Howard, C. Abell, W. Blakemore et al. // Journal of Medicinal Chemistry. – 2006. – Vol. 49, Issue 4. – P. 1346−1355. doi : 10.1021/jm050850v.
  55. Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase / A. W, Hung, H. L. Silvestre, S. Wen et al. // Angewandte Chemie International Edition. – 2009. – Vol. 48, Issue 45. – P. 8452−8456. doi : 10.1002/anie.200903821.
  56. Verdonk, M. L. Group efficiency: A guideline for hits–to–leads chemistry / M. L. Verdonk, D. C. Rees // ChemMedChem. – 2008. – Vol. 3, Issue 8. – P. 1179−1180. doi : 10.1002/cmdc.200800132.
  57. Discovery of cell–active phenyl–imidazole Pin1 inhibitors by structure–guided fragment evolution / A. Potter, V. Oldfield, C. Nunns et al. // Bioorganic & Medicinal Chemistry Letters. – 2010. – Vol. 20, Issue 22. – P. 6483−6488. doi : 10.1016/j.bmcl.2010.09.063.
  58. Fragment–based discovery of the pyrazol–4–yl urea (AT9283), a multitargeted kinase inhibitor with potent Aurora kinase activity / S. Howard, V. Berdini, J. A. Boulstridge et al. // Journal of Medicinal Chemistry. – 2009. – Vol. 52, Issue 2. – P. 379−388. doi : 10.1021/jm800984v.
  59. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib–resistant BCR–ABL–positive leukemic cells / R. Tanaka, M. S. Squires, S. Kimura et al. // Blood. – 2010. – Vol. 116, Issue 12. – P. 2089−2095. doi : 10.1182/blood–2009–03–211466.
  60. Erlanson, D. A. Fragment–based drug discovery / D. A. Erlanson, R. S. McDowell, T. O’Brien // Journal of Medicinal Chemistry. – 2004. – Vol. 47, Issue 14. – P. 3463–3482. doi : 10.1021/jm040031v.
  61. Fragment–based lead discovery / D. C. Rees, M. Congreve, C. W. Murray et al. // Nature Reviews Drug Discovery. – 2004. – Vol. 3, Issue 8. – P. 660–672. doi : 10.1038/nrd1467.
  62. Vemurafenib: the first drug approved for BRAF–mutant cancer / G. Bollag, J. Tsai, J. Zhang et al. // Nature Reviews Drug Discovery. – 2012. – Vol. 11, Issue 11. – P. 873–886. doi : 10.1038/nrd3847
  63. Efremov,I.V. Fragment–Based Lead Generation. Lead Generation: Methods and Strategies (67, 10) /I.V. Efremov, D. A. Erlanson. – Wiley–VCH, 2016. – P. 133.
  64. Scaffold–based discovery of indeglitazar, a PPAR pan–active anti–diabetic agent / D. R. Artis, J. J. Lin, C. Zhang et al. // Proceedings of the National Academy of Sciences. – 2008. – Vol. 106, Issue 1. – P.262–267. doi : 10.1073/pnas.0811325106.

Downloads

Published

2017-03-23

How to Cite

(1)
Kryshchyshyn, A. P. Fragment-Based Drug Design (FBDD). J. Org. Pharm. Chem. 2017, 15, 28-44.

Issue

Vol. 15 No. 1(57) (2017)

Section

Original Researches

License

Copyright (c) 2017 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).