Fragment-based lead discovery

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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] This methodology could help to design multitarget drugs for multiple diseases. The multitarget inhibitor approach is based on designing an inhibitor for the multiple targets. This type of drug design opens up new polypharmacological avenues for discovering innovative and effective therapies. Neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s, among others, also show rather complex etiopathologies. Multitarget inhibitors are more appropriate for addressing the complexity of AD and may provide new drugs for controlling the multifactorial nature of AD, stopping its progression. [3]

Library design[edit]

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).[4] 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[edit]

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,[5][6] protein-observe NMR methods such as 1H-15N heteronuclear single quantum coherence (HSQC) that utilises isotopically-labelled proteins,[7] surface plasmon resonance (SPR),[8] isothermal titration calorimetry (ITC)[9] and Microscale Thermophoresis (MST)[10] are routinely-used for ligand screening and for the quantification of fragment binding affinity to the target protein. At modern X-ray crystallography synchrotron beamlines, several hundred data sets of protein-ligand complex crystal structures can be obtained within 24 hours. This technology makes crystallographic fragment screening possible, i.e. the use of X-ray crystallography directly for the fragment screening step.[11]

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.[12][13] Such information can then be used to guide organic synthesis for high-affinity protein ligands and enzyme inhibitors.[14]

Advantages over traditional libraries[edit]

Advantages of screening low molecular weight fragment based libraries over traditional higher molecular weight chemical libraries are several.[15] 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[edit]


  1. ^ a b Price AJ, Howard S, Cons BD (November 2017). "Fragment-based drug discovery and its application to challenging drug targets". Essays in Biochemistry. 61 (5): 475–484. doi:10.1042/EBC20170029. PMID 29118094.
  2. ^ Tounge BA, Parker MH (2011). "Designing a Diverse High-Quality Library for Crystallography-Based FBDD Screening". Fragment-Based Drug Design - Tools, Practical Approaches, and Examples. Methods in Enzymology. Vol. 493. pp. 3–20. doi:10.1016/B978-0-12-381274-2.00001-7. ISBN 9780123812742. PMID 21371585.
  3. ^ Gharaghani S, Khayamian T, Ebrahimi M (October 2013). "Multitarget fragment-based design of novel inhibitors for AChE and SSAO/VAP-1 enzymes". Journal of Chemometrics. 27 (10): 297–305. doi:10.1002/cem.2556. S2CID 86409773.
  4. ^ Congreve M, Carr R, Murray C, Jhoti H (October 2003). "A 'rule of three' for fragment-based lead discovery?". Drug Discov. Today. 8 (19): 876–7. doi:10.1016/S1359-6446(03)02831-9. PMID 14554012.
  5. ^ Ma R, Wang P, Wu J, Ruan K (July 2016). "Process of Fragment-Based Lead Discovery-A Perspective from NMR". Molecules. 21 (7): 854. doi:10.3390/molecules21070854. PMC 6273320. PMID 27438813.
  6. ^ Norton RS, Leung EW, Chandrashekaran IR, MacRaild CA (July 2016). "Applications of (19)F-NMR in Fragment-Based Drug Discovery". Molecules. 21 (7): 860. doi:10.3390/molecules21070860. PMC 6273323. PMID 27438818.
  7. ^ Harner MJ, Frank AO, Fesik SW (June 2013). "Fragment-based drug discovery using NMR spectroscopy". Journal of Biomolecular NMR. 56 (2): 65–75. doi:10.1007/s10858-013-9740-z. PMC 3699969. PMID 23686385.
  8. ^ Neumann T, Junker HD, Schmidt K, Sekul R (Aug 2007). "SPR-based fragment screening: advantages and applications". Current Topics in Medicinal Chemistry. 7 (16): 1630–1642. doi:10.2174/156802607782341073. PMID 17979772. S2CID 17637118.
  9. ^ Silvestre HL, Blundell TL, Abell C, Ciulli A (August 2013). "Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery". Proceedings of the National Academy of Sciences of the United States of America. 110 (32): 12984–12989. Bibcode:2013PNAS..11012984S. doi:10.1073/pnas.1304045110. PMC 3740835. PMID 23872845.
  10. ^ Coletti A, Camponeschi F, Albini E, Greco FA, Maione V, Custodi C, et al. (December 2017). "Fragment-based approach to identify IDO1 inhibitor building blocks". European Journal of Medicinal Chemistry. 141: 169–177. doi:10.1016/j.ejmech.2017.09.044. PMID 29031064.
  11. ^ Patel D, Bauman JD, Arnold E (Aug 2014). "Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery". Progress in Biophysics and Molecular Biology. 116 (2–3): 92–100. doi:10.1016/j.pbiomolbio.2014.08.004. PMID 25117499.
  12. ^ Caliandro R, Belviso DB, Aresta BM, de Candia M, Altomare CD (June 2013). "Protein crystallography and fragment-based drug design". Future Med. Chem. 5 (10): 1121–40. doi:10.4155/fmc.13.84. PMID 23795969.
  13. ^ Chilingaryan Z, Yin Z, Oakley AJ (Oct 2012). "Fragment-based screening by protein crystallography: successes and pitfalls". Int. J. Mol. Sci. 13 (10): 12857–79. doi:10.3390/ijms131012857. PMC 3497300. PMID 23202926.
  14. ^ de Kloe GE, Bailey D, Leurs R, de Esch IJ (Jul 2009). "Transforming fragments into candidates: small becomes big in medicinal chemistry". Drug Discov. Today. 14 (13–14): 630–46. doi:10.1016/j.drudis.2009.03.009. PMID 19443265.
  15. ^ Erlanson DA, McDowell RS, O'Brien T (July 2004). "Fragment-based drug discovery". J. Med. Chem. 47 (14): 3463–82. doi:10.1021/jm040031v. PMID 15214773. S2CID 15138472.

Further reading[edit]

  • Folkers G, Jahnke W, Erlanson DA, Mannhold R, Kubinyi H (2006). Fragment-based Approaches in Drug Discovery (Methods and Principles in Medicinal Chemistry). Weinheim: Wiley-VCH. ISBN 978-3-527-31291-7.
  • Everts S (2008-07-21). "Piece By Piece". Chemical and Engineering News. 86 (29): 15–23. doi:10.1021/cen-v086n029.p015.
  • Kuo LC (2011). Fragment Based Drug Design, Volume V493: Tools, Practical Approaches, and Examples (Methods in Enzymology). Boston: Academic Press. ISBN 978-0-12-381274-2.
  • Erlanson DA (June 2011). "Introduction to Fragment-Based Drug Discovery". Fragment-Based Drug Discovery and X-Ray Crystallography. Top Curr Chem. Topics in Current Chemistry. Vol. 317. pp. 1–32. doi:10.1007/128_2011_180. ISBN 978-3-642-27539-5. PMID 21695633.
  • Edward Zartler; Michael Shapiro (2008). Fragment-based drug discovery a practical approach. Wiley.