The benefits of constructing leads from fragment hits

Future Medicinal Chemistry

Volumn 3, Issue 9, 2011, Pages 1111-1115

  Foloppe, N ^a  

^a Vernalis PLC   (United Kingdom)

Author keywords

computational chemistry; de novo; drug design; fragment; hit to lead

Indexed keywords

LEAD;

BINDING AFFINITY; BINDING COMPETITION; BINDING SITE; CHEMICAL ANALYSIS; CHEMICAL REACTION; COMBINATORIAL CHEMISTRY; FRAGMENT BASED DRUG DISCOVERY; HIGH THROUGHPUT SCREENING; HIT TO LEAD; HYBRIDIZATION; PRIORITY JOURNAL; RECEPTOR BINDING; REVIEW;

COMPUTER SIMULATION; DRUG DESIGN; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; HUMANS; MOLECULAR STRUCTURE; PEPTIDE FRAGMENTS; PROTEIN BINDING; SMALL MOLECULE LIBRARIES;

EID: 79961039537     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.11.46     Document Type: Review

References (44)

1. Rees DC, Congreve M, Murray CW, Carr R. Fragment-based lead discovery. Nat. Rev. Drug Discov. 3, 660-672 (2004). (Pubitemid 39173507)
2. Hubbard RE, Davis B, Chen I, Drysdale MJ. The SeeDs approach: integrating fragments into drug discovery. Curr. Top. Med. Chem. 7, 1568-1581 (2007). (Pubitemid 350131015)
3. de Esch IJP. The HTS dogma is shattered, and now there are fragments everywhere. Drug Discov. Today Technol. 7, e147-e148 (2010).
4. Hajduk PJ, Greer J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 6, 211-219 (2007). (Pubitemid 46344625)
5. Fragment-Based Drug Design. Tools, Practical Approaches, and Examples. Kuo LC (Ed.).Elsevier, San Diego, CA, USA (2011).
6. Card GL, Blasdel L, England BP et al. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat. Biotechnol. 23, 201-207 (2005). (Pubitemid 40255330)
7. Congreve M, Carr R, Murray C, Jhoti H. A 'Rule of Three' for fragment-based lead discovery? Drug Discov. Today 8, 876-877 (2003). (Pubitemid 37194496)
8. Congreve M, Chessari G, Tisi D, Woodhead AJ. Recent developments in fragment-based drug discovery. J. Med. Chem. 51, 3661-3680 (2008). (Pubitemid 351956496)
9. Whittaker M, Law RJ, Ichihara O, Hesterkamp T, Hallett D. Fragments: past, present and future. Drug Discov. Today Technol. 7, e163-e171 (2010).
10. Chessari G, Woodhead AJ. From fragment to clinical candidate - a historical perspective. Drug Discov. Today 14, 299-307 (2009).
11. Artis DR, Lina JJ, Zhanga C et al. Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc. Natl Acad. Sci. USA 106, 262-267 (2009).
12. Hajduk PJ, Galloway WRJD, Spring D. A question of library design. Nature 470, 42-43 (2011).
13. Brough PA, Barril X, Borgognoni J et al. 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 (2009).
14. Hubbard RE, Murray JB. Experiences in fragment-based lead discovery. In:Fragment- Based Drug Design. Tools, Practical Approaches, and Examples , Kuo LC (Ed.).Elsevier Inc., Amsterdam 509-531 (2001).
15. Murray CW, Blundell TL. Structural biology in fragment-based drug design. Curr. Opin. Struct. Biol. 20(497-507), (2010).
16. Michne WF. Hit-to-lead chemistry: a key element in new lead generation. Pharmaceutical News 3, 19-21 (1996).
17. Baurin N, Aboul-Ela F, Barril X et al. Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. J. Chem. Inf. Comput. Sci. 44, 2157-2166 (2004).
18. Retra K, Irth H, van Muijlwijk-Koezen JE. Surface plasmon resonance biosensor analysis as a useful tool in FBDD. Drug Discov. Today Technol. 7, e181-e187 (2010).
19. Antonysamy SS, Aubol B, Blaney J et al. Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors. Bioorg. Med. Chem. Lett. 18, 2990-2995 (2008). (Pubitemid 351608863)
20. Edink E, Jansen C, Leurs R, de Esch IJP. The heat is on: thermodynamic analysis in fragment-based drug discovery. Drug Discov. Today Technol. 7, e189-e201 (2010).
21. Blundell TL, Jhoti H, Abell C. High-throughput crystallography for lead discovery in drug design. Nat. Rev. Drug Discov. 11, 45-54 (2002). (Pubitemid 37361403)
22. Hann MM, Leach AR, 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).
23. Chen I, Hubbard RE. Lessons from fragment library design: analysis of output from multiple screening campains. J. Comput. Aided Mol. Des. 23, 603-620 (2009).
24. Hopkins AL, Groom CR, Alex A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 9, 430-431 (2004). (Pubitemid 38510559)
25. Hajduk PJ. Fragment-based drug design: how big is too big? J. Med. Chem. 49, 6972-6976 (2006). (Pubitemid 44885985)
26. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Reviews 23, 3-25 (1997). (Pubitemid 27046991)
27. Potter A, Oldfield V, Nunns C et al. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution. Bioorg. Med. Chem. Lett. 20, 6483-6488 (2010).
28. Barker JJ, Barker O, Courtney SM et al. Discovery of a novel Hsp90 inhibitor by fragment linking. ChemMedChem 5, 1697-1700 (2010).
29. Barker JJ, Barker O, Boggio R et al. Fragment-based identification of Hsp90 inhibitors. ChemMedChem 4, 963-966 (2009).
30. Tsai J, Lee JT, Wang W et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl Acad. Sci. USA 105, 3041-3046 (2008). (Pubitemid 351723664)
31. Hajduk PJ. Puzzling through fragment-based drug design. Nat. Chem. Biol. 2, 658-659 (2006). (Pubitemid 44764204)
32. Babaoglu K, Shoichet BK. Deconstructing fragment-based inhibitor discovery. Nat. Chem. Biol. 2, 720-723 (2006). (Pubitemid 44764214)
33. Pierce AC, Rao G, Bemis GW. BREED: generating novel inhibitors through hybridization of known ligands. Application to CDK2, P38, and HIV protease. J. Med. Chem. 47, 2768-2775 (2004). (Pubitemid 38656730)
34. Ferrara P, Gohlke H, Price DJ, Klebe G, Brooks CLI. Assessing scoring functions for protein-ligand interactions. J. Med. Chem. 47, 3032-3047 (2004). (Pubitemid 38702700)
35. Schneider G, Fechner U. Computer-based de novo design of drug-like molecules. Nat. Rev. Drug Discov. 4, 649-663 (2005). (Pubitemid 41149759)
36. Loving K, Alberts I, Sherman W. Computational approaches for fragment-based and de novo design. Curr. Top. Med. Chem. 10, 14-32 (2010).
37. Hung A, Silvestre H, Wen S, Ciulli A, Blundell T, Abell C. Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angew. Chem. Int. Ed. 48, 8452-8456 (2009).
38. Chung S, Parker JB, Bianchet M, Amzel M, Stivers JT. Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nat. Chem. Biol. 5, 407-413 (2009).
39. Thompson DC, Denny RA, Nilakantan R, Humblet C, Joseph-McCarthy D, Feyfant E. CONFIRM: connecting fragments found in receptor molecules. J. Comput. Aided Mol. Des. 22, 761-772 (2008).
40. Jencks WP. On the attribution and additivity of binding energies. Proc. Natl Acad. Sci. USA 78, 4046-4050 (1981). (Pubitemid 11010286)
41. Murray CW, Verdonk ML. The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J. Comput. Aided Mol. Des. 16, 741-753 (2002). (Pubitemid 36336183)
42. Foloppe N, Hubbard R. Towards predictive ligand design with free-energy based computational methods? Curr. Med. Chem. 13, 3583-3608 (2006). (Pubitemid 44873749)
43. Foloppe N, Chen I. Conformational sampling and energetics of drug-like molecules. Curr. Med. Chem. 16, 3381-3413 (2009).
44. Roughley SD, Hubbard RE. How well can fragments explore accessed chemical space? A case study from heat shock protein 90. J. Med. Chem. 54, 3989-4005 (2011).