Fragment-based lead discovery

Nature Reviews Drug Discovery

Volumn 3, Issue 8, 2004, Pages 660-672

  Ress, David C ^a   Congreve, Miles ^a   Murray, Christopher W ^a   Carr, Robin ^a  

^a ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AVIDIN; CASPASE; CASPASE INHIBITOR; CHOLINESTERASE; CHOLINESTERASE INHIBITOR; DNA TOPOISOMERASE (ATP HYDROLYSING); FATTY ACID BINDING PROTEIN; FK 506 BINDING PROTEIN; GYRASE INHIBITOR; METHYLTRANSFERASE; METHYLTRANSFERASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38; PLASMINOGEN ACTIVATOR INHIBITOR; PROTEIN INHIBITOR; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PROTEIN TYROSINE PHOSPHATASE 1B; PROTEIN TYROSINE PHOSPHATASE 1B INHIBITOR; RIBOSOME RNA; RNA DERIVATIVE; STROMELYSIN; STROMELYSIN INHIBITOR; TACROLIMUS; THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE INHIBITOR; TRYPTASE; TRYPTASE INHIBITOR; UNINDEXED DRUG; VANCOMYCIN; PEPTIDE FRAGMENT;

BINDING AFFINITY; DRUG BINDING SITE; DRUG DETERMINATION; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; MOLECULAR WEIGHT; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY; CHEMISTRY; DRUG SCREENING; METABOLISM; METHODOLOGY; PHARMACEUTICS;

CHEMISTRY, PHARMACEUTICAL; DRUG EVALUATION, PRECLINICAL; PEPTIDE FRAGMENTS; STRUCTURE-ACTIVITY RELATIONSHIP; TECHNOLOGY, PHARMACEUTICAL;

EID: 4344592378     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1467     Document Type: Review

References (53)

1. Boehm, H. J. et al. 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, 2664-2674 (2000).
2. Fejzo, J. et al. The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. Chem. Biol. 6, 755-769 (1999).
3. Maly, D. J., Choong, I. C. & Ellman, J. A. Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors. Proc. Natl Acad. Sci. USA 97, 2419-2424 (2000).
4. Liebeschuetz, J. W. et al. PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors. J. Med. Chem. 45, 1221-1232 (2002).
5. Jencks, W. P. On the attribution and additivity of binding energies. Proc. Natl Acad. Sci. USA 78, 4046-4050 (1981).
6. Farmer, P. S. & Ariens, E. J. Speculations on the design of nonpeptidic peptidomimetics. Trends Pharmacol. Sci. 3, 362-365 (1982).
7. Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531-1534 (1996).
8. Pellecchia, M., Sem, D. S. & Wuthrich, K. NMR in drug discovery, Nature Rev. Drug Discov. 1, 211-219 (2002).
9. Kuhn, P., Wilson, K., Patch, M. G. & Stevens, R. C. The genesis of high-throughput structure-based drug discovery using protein crystallography. Curr. Opin. Chem. Biol. 6, 704-710 (2002).
10. Blundell, T. L., Jhoti, H. & Abell, C. High-throughput crystallography for lead discovery in drug design. Nature Rev. Drug Discov. 1, 45-54 (2002).
11. Hann, M. M., Leach, A. R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856-864 (2001).
12. Oprea, T. I., Davis, A. M., Teague, S. J. & Leeson, P. D. Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci. 41, 1308-1315 (2001).
13. Teague, S. J., Davis, A. M., Leeson, P D. & Oprea, T. The design of leadlike combinatorial libraries. Angew. Chem. Int. Ed. Engl. 38, 3743-3748 (1999).
14. Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M. & Leeson, P. D. A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 46, 1250-1256 (2003).
15. Vieth, M. et al. Characteristic physical properties and structural fragments of marketed oral drugs. J. Med. Chem. 47, 224-232 (2004).
16. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3-26 (2001).
17. Veber, D. F. et al. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615-2623 (2002).
18. Congreve, M., Carr, R., Murray, C. & Jhoti, H. A 'rule of three' for fragment-based lead discovery? Drug Discov. Today 8, 876-877 (2003).
19. Erlanson, D. A. et al. Site-directed ligand discovery. Proc. Natl Acad. Sci. USA 97, 9367-9372 (2000).
20. Frederickson, M., Gill, A. L., Padova, A. & Congreve, M. S. Preparation of indoles as p38 MAP kinase inhibitors. Astex Technology Limited, UK. UK Patent WO 03/087087 (2003).
21. Wendt, M. D. et al. Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase: synthesis, structural analysis, and sar of N-phenyl amide 6-substitution. J. Med. Chem. 47, 303-324 (2004).
22. Bohm, H. J., Banner, D. W. & Weber, L. Combinatorial docking and combinatorial chemistry: design of potent non-peptide thrombin inhibitors. J. Comput. Aided Mol. Des. 13, 51-56 (1999).
23. van Dongen, M. J. P. et al. Structure-based screening as applied to human FABP4: a highly efficient alternative to HTS for hit generation. J. Am. Chem. Sec. 124, 11874-11880 (2002).
24. Hajduk, P. J. et al. Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis. J. Med. Chem. 42, 3852-3859 (1999).
25. Murray, C. W. & Verdonk, M. L. The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J. Comput. Aided Mol. Des. 16, 741-753 (2002).
26. Green, N. M. Avidin. Adv. Protein Chem. 29, 85-133 (1975).
27. Rao, J., & Whitesides, G. M. Tight binding of a dimeric derivative of vancomycin with dimeric L-Lys-D-Ala-D-Ala. J. Am. Chem. Soc. 119, 10286-10290 (1997).
28. Rao, J., Lahiri, J., Weis, R. M. & Whitesides, G. M. Design, synthesis, and characterization of a high-affinity trivalent system derived from vancomycin and L-Lys-D-Ala-D-Ala. J. Am. Chem. Soc. 122, 2698-2710 (2000).
29. Pang, Y. P., Quiram, P., Jelacic, T., Hong, F. & Brimijoin, S. Highly potent, selective, and low cost bistetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease. J. Biol. Chem. 271, 23646-23649 (1996).
30. Pereira, P. J. et al. Human β-tryptase is a ring-like tetramer with active sites facing a central pore. Nature 392, 306-311 (1998).
31. Burgess, L. E. et al. Potent selective nonpeptidic inhibitors of human lung tryptase. Proc. Natl Acad. Sci. USA 96, 8348-8352 (1999).
32. Rice, K. D. et al. Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity. Bioorg. Med. Chem. Lett. 10, 2361-2366 (2000).
33. Hajduk, P. J. et al. Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J. Am. Chem. Soc. 119, 5818-5827 (1997).
34. Erlanson, D. A. et al. In situ assembly of enzyme inhibitors using extended tethering. Nature Biotechnol. 21, 308-314 (2003).
35. Szczepankiewicz, B. G. et al. Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J. Am. Chem. Sec. 125, 4087-4096 (2003).
36. Liu, G. et al. Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J. Med. Chem. 46, 4232-4235 (2003).
37. Swayze, E. E. et al. SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets. J. Med. Chem. 45, 3816-3819 (2002).
38. Braisted, A. C. et al. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J. Am. Chem. Soc. 125, 3714-3715 (2003).
39. Ramstrom, O. & Lehn, J. M. Drug discovery by dynamic combinatorial libraries. Nature Rev. Drug Discov. 1, 26-36 (2002).
40. Huc, I. & Lehn, J. M. Virtual combinatorial libraries: dynamic generation of molecular and supramolecular diversity by self-assembly Proc. Natl Acad. Sci. USA 94, 2106-2110 (1997).
41. Hochgurtel, M. et al. Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological target. J. Med. Chem. 46, 356-358 (2003).
42. Hochgurtel, M. et al. Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries. Proc. Natl Acad. Sci. USA 99, 3382-3387 (2002).
43. Congreve, M. S. et al. Detection of ligands from a dynamic combinatorial library by X-ray crystallography. Angew. Chem. Int. Ed. Engl. 42, 4479-4482 (2003).
44. Bourne, Y. et al. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation. Proc. Natl Acad. Sci. USA 101, 1449-1454 (2004).
45. Lewis, W. G. et al. Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew. Chem. Int. Ed. Engl. 41, 1053-1057 (2002).
46. Hajduk, P. J. et al. Identification of novel inhibitors of urokinase via NMR-based screening. J. Med. Chem. 43, 3862-3866 (2000).
47. Nienaber, V. L. et al. Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nature Biotechnol. 18, 1105-1108 (2000).
48. Lesuisse, D. et al. SAR and X-ray, A new approach combining fragment-based screening and rational drug design: application to the discovery of nanomolar inhibitors of Src SH2. J. Med. Chem. 45, 2379-2387 (2002).
49. Lange, G. et al. Requirements for specific binding of low affinity inhibitor fragments to the SH2 domain of (pp60)Src are identical to those for high affinity binding of full length inhibitors. J. Med. Chem. 46, 5184-5195 (2003).
50. Hajduk, P. J. et al. Design of adenosine kinase inhibitors from the NMR-based screening of fragments. J. Med. Chem. 43, 4781-4786 (2000).
51. Hopkins, A. L, Groom, C. R & Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 9, 430-431 (2004).
52. Erlanson, D. A., McDowell, R. S. & O'Brien, T. Fragment-based drug discovery. J. Med. Chem. 47, 3463-3482 (2004).
53. Teague, S. J. Implications of protein flexibility for drug discovery. Nature Rev. Drug Discov. 2, 527-541 (2003).