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词条 Fragment-based lead discovery
释义

  1. Library design

  2. Library screening and quantification

  3. Advantages over traditional libraries

  4. See also

  5. References

  6. Further reading

Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in molecular weight.[1] It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity. FBLD can be compared with high-throughput screening (HTS). In HTS, libraries with up to millions of compounds, with molecular weights of around 500 Da, are screened, and nanomolar binding affinities are sought. In contrast, in the early phase of FBLD, libraries with a few thousand compounds with molecular weights of around 200 Da may be screened, and millimolar affinities can be considered useful.[2] FBLD is a technique being used in research for discovering novel potent inhibitors.[1]

Library design

In analogy to the rule of five, it has been proposed that ideal fragments should follow the 'rule of three' (molecular weight < 300, ClogP < 3, the number of hydrogen bond donors and acceptors each should be < 3 and the number of rotatable bonds should be < 3).[3] Since the fragments have relatively low affinity for their targets, they must have high water solubility so that they can be screened at higher concentrations.

Library screening and quantification

In fragment-based drug discovery, the low binding affinities of the fragments pose significant challenges for screening. Many biophysical techniques have been applied to address this issue. In particular, ligand-observe nuclear magnetic resonance (NMR) methods such as water-ligand observed via gradient spectroscopy (waterLOGSY), saturation transfer difference spectroscopy (STD-NMR), 19F NMR spectroscopy and inter-ligand Overhauser effect (ILOE) spectroscopy,[4][5] protein-observe NMR methods such as 1H-15N heteronuclear single quantum coherence (HSQC) that utilises isotopically-labelled proteins,[6] surface plasmon resonance (SPR)[7] and isothermal titration calorimetry (ITC)[8] are routinely-used for ligand screening and for the quantification of fragment binding affinity to the target protein.

Once a fragment (or a combination of fragments) have been identified, protein X-ray crystallography is used to obtain structural models of the protein-fragment(s) complexes.[9][10] Such information can then be used to guide organic synthesis for high-affinity protein ligands and enzyme inhibitors.[11]

Advantages over traditional libraries

Advantages of screening low molecular weight fragment based libraries over traditional higher molecular weight chemical libraries are several.[12] These include:

  • More hydrophilic hits in which hydrogen bonding is more likely to contribute to affinity (enthalpically driven binding). It is generally much easier to increase affinity by adding hydrophobic groups (entropically driven binding); starting with a hydrophilic ligand increases the chances that the final optimized ligand will not be too hydrophobic (log P < 5).
  • Higher ligand efficiency so that the final optimized ligand will more likely be relatively low in molecular weight (MW < 500).
  • Since two to three fragments in theory can be combined to form an optimized ligand, screening a fragment library of N compounds is equivalent to screening N2 - N3 compounds in a traditional library.
  • Fragments are less likely to contain sterically blocking groups that interfere with an otherwise favorable ligand-protein interaction, increasing the combinatorial advantage of a fragment library even further.

See also

  • Druglikeness
  • Protein-directed dynamic combinatorial chemistry
  • Lipinski's rule of five

References

1. ^1 {{cite journal | vauthors = Price AJ, Howard S, Cons BD | title = Fragment-based drug discovery and its application to challenging drug targets | journal = Essays in Biochemistry | volume = 61 | issue = 5 | pages = 475–484 | date = November 2017 | pmid = 29118094 | doi = 10.1042/EBC20170029 }}
2. ^{{Cite book| doi = 10.1016/B978-0-12-381274-2.00001-7| pmid = 21371585| chapter = Designing a Diverse High-Quality Library for Crystallography-Based FBDD Screening| title = Fragment-Based Drug Design - Tools, Practical Approaches, and Examples| volume = 493| pages = 3–20| series = Methods in Enzymology| year = 2011| last1 = Tounge| first1 = Brett A| last2 = Parker| first2 = Michael H| isbn = 9780123812742}}
3. ^{{cite journal | vauthors = Congreve M, Carr R, Murray C, Jhoti H | title = A 'rule of three' for fragment-based lead discovery? | journal = Drug Discov. Today | volume = 8 | issue = 19 | pages = 876–7 |date=October 2003 | pmid = 14554012 | doi = 10.1016/S1359-6446(03)02831-9 | url = http://www.sciencedirect.com/science/article/pii/S1359644603028319 }}
4. ^{{cite journal | vauthors = Ma R, Wang P, Wu J, Ruan K | title = Process of Fragment-Based Lead Discovery — A Perspective from NMR | journal = Molecules | volume = 21 | issue = 7 | pages = 854 |date=July 2016 | pmid = 27438813| pmc = 6273320 | doi = 10.3390/molecules21070854 | url = http://www.mdpi.com/1420-3049/21/7/854 }}
5. ^{{cite journal | vauthors = Norton RS, Leung EW, Chandrashekaran IR, MacRaild CA | title = Applications of 19F-NMR in Fragment-Based Drug Discovery | journal = Molecules | volume = 21 | issue = 7 | pages = 860 |date=July 2016 | pmid = 27438818| pmc = 6273323 | doi = 10.3390/molecules21070860 | url = http://www.mdpi.com/1420-3049/21/7/860 }}
6. ^{{cite journal | vauthors = Harner MJ, Frank AO, Fesik SW | title = Fragment-based drug discovery using NMR spectroscopy | journal = J. Biomol. NMR | volume = 56 | issue = 2 | pages = 65–75 |date=June 2013 | pmid = 23686385 | doi = 10.1007/s10858-013-9740-z | pmc=3699969}}
7. ^{{cite journal | vauthors = Neumann T, Junker HD, Schmidt K, Sekul R | title = SPR-based fragment screening: advantages and applications | journal = Curr. Top. Med. Chem. | volume = 7 | issue = 16 | pages = 1630–42 |date=Aug 2007 | pmid = 17979772 | doi = 10.2174/156802607782341073| url = http://www.ingentaconnect.com/content/ben/ctmc/2007/00000007/00000016/art00007 }}
8. ^{{cite journal | vauthors = Silvestre HL, Blundell TL, Abell C, Ciulli A | title = Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery | journal = Proc. Natl. Acad. Sci. USA | volume = 110 | issue = 32 | pages = 12984–9 |date=Aug 2013 | pmid = 23872845 | doi = 10.1073/pnas.1304045110 | url = http://www.pnas.org/content/110/32/12984.short | pmc=3740835}}
9. ^{{cite journal | vauthors = Caliandro R, Belviso DB, Aresta BM, de Candia M, Altomare CD | title = Protein crystallography and fragment-based drug design | journal = Future Med. Chem. | volume = 5 | issue = 10 | pages = 1121–40 |date=June 2013 | pmid = 23795969 | doi = 10.4155/fmc.13.84 }}
10. ^{{cite journal | vauthors = Chilingaryan Z, Yin Z, Oakley AJ | title = Fragment-based screening by protein crystallography: successes and pitfalls | journal = Int. J. Mol. Sci. | volume = 13 | issue = 10 | pages = 12857–79 |date=Oct 2012 | pmid = 23202926 | doi = 10.3390/ijms131012857 | url = http://www.mdpi.com/1422-0067/13/10/12857 | pmc=3497300}}
11. ^{{cite journal | vauthors = de Kloe GE, Bailey D, Leurs R, de Esch IJ | title = Transforming fragments into candidates: small becomes big in medicinal chemistry | journal = Drug Discov. Today | volume = 14 | issue = 13–14 | pages = 630–46 |date=Jul 2009 | pmid = 19443265 | doi = 10.1016/j.drudis.2009.03.009 | url = http://www.sciencedirect.com/science/article/pii/S1359644609001111 }}
12. ^{{cite journal | vauthors = Erlanson DA, McDowell RS, O'Brien T | title = Fragment-based drug discovery | journal = J. Med. Chem. | volume = 47 | issue = 14 | pages = 3463–82 |date=July 2004 | pmid = 15214773 | doi = 10.1021/jm040031v }}

Further reading

{{refbegin}}
  • {{cite book | vauthors = Folkers G, Jahnke W, Erlanson DA, Mannhold R, Kubinyi H | title = Fragment-based Approaches in Drug Discovery (Methods and Principles in Medicinal Chemistry) | publisher = Wiley-VCH | location = Weinheim | year = 2006 | pages = | isbn = 978-3-527-31291-7 }}
  • {{cite journal | journal = Chemical and Engineering News | date= 2008-07-21 | issue = 29 | pages = 15–23 | title = Piece By Piece | author = Everts S | volume = 86 | doi = 10.1021/cen-v086n029.p015 }}
  • {{cite book | author = Kuo LC | title = Fragment Based Drug Design, Volume V493: Tools, Practical Approaches, and Examples (Methods in Enzymology) | publisher = Academic Press | location = Boston | year = 2011 | pages = | isbn = 978-0-12-381274-2 | oclc = | doi = | accessdate = }}
  • {{cite book | author = Erlanson DA | title = Introduction to Fragment-Based Drug Discovery | journal = Top Curr Chem | volume = 317| issue = | pages = 1–32|date=June 2011 | pmid = 21695633 | doi = 10.1007/128_2011_180 | series = Topics in Current Chemistry | isbn = 978-3-642-27539-5 }}
  • {{cite book | author = Edward Zartler | author2 = Michael Shapiro | title = Fragment-based drug discovery a practical approach | publisher = Wiley | year = 2008 }}
{{refend}}
  • [https://www.specs.net/transfer.php?code=SPECSpQyBJSyREKIGZJEuqTSvLKAypl9DpzIjoTS0MJEsEaWuM21yoaDgDzSmMJEsGTyvpzSlrF56nKO8H3OyL3AcFRSvnTMlHHqj Download an example of a Fragment based library here (4,532 compounds, zipped SD-File)]
{{DEFAULTSORT:Fragment-Based Lead Discovery}}

2 : Drug discovery|Biotechnology
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