Fragment-based lead discovery

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).{{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 }} 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.

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),{{Cite journal |last=Lang |first=Stuart |last2=Fletcher |first2=Daniel A. |last3=Petit |first3=Alain-Pierre |last4=Luise |first4=Nicola |last5=Fyfe |first5=Paul |last6=Zuccotto |first6=Fabio |last7=Porter |first7=David |last8=Hope |first8=Anthony |last9=Bellany |first9=Fiona |last10=Kerr |first10=Catrina |last11=Mackenzie |first11=Claire J. |last12=Wyatt |first12=Paul G. |last13=Gray |first13=David W. |date=2024 |title=Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202400025 |journal=ChemMedChem |language=en |volume=19 |issue=13 |pages=e202400025 |doi=10.1002/cmdc.202400025 |issn=1860-7187}} saturation transfer difference spectroscopy (STD-NMR), ¹⁹F NMR spectroscopy and inter-ligand Overhauser effect (ILOE) spectroscopy,{{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 | doi-access = free }}{{cite journal | vauthors = Norton RS, Leung EW, Chandrashekaran IR, MacRaild CA | title = Applications of (19)F-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 | doi-access = free }} protein-observe NMR methods such as ¹H-¹⁵N heteronuclear single quantum coherence (HSQC) that utilises isotopically labelled proteins,{{cite journal | vauthors = Harner MJ, Frank AO, Fesik SW | title = Fragment-based drug discovery using NMR spectroscopy | journal = Journal of Biomolecular NMR | volume = 56 | issue = 2 | pages = 65–75 | date = June 2013 | pmid = 23686385 | pmc = 3699969 | doi = 10.1007/s10858-013-9740-z }} surface plasmon resonance (SPR),{{cite journal | vauthors = Neumann T, Junker HD, Schmidt K, Sekul R | title = SPR-based fragment screening: advantages and applications | journal = Current Topics in Medicinal Chemistry | volume = 7 | issue = 16 | pages = 1630–1642 | date = Aug 2007 | pmid = 17979772 | doi = 10.2174/156802607782341073 | s2cid = 17637118 }} isothermal titration calorimetry (ITC){{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 32 | pages = 12984–12989 | date = August 2013 | pmid = 23872845 | pmc = 3740835 | doi = 10.1073/pnas.1304045110 | doi-access = free | bibcode = 2013PNAS..11012984S }} and Microscale Thermophoresis (MST){{cite journal | vauthors = Coletti A, Camponeschi F, Albini E, Greco FA, Maione V, Custodi C, Ianni F, Grohmann U, Orabona C, Cantini F, Macchiarulo A | display-authors = 6 | title = Fragment-based approach to identify IDO1 inhibitor building blocks | journal = European Journal of Medicinal Chemistry | volume = 141 | pages = 169–177 | date = December 2017 | pmid = 29031064 | doi = 10.1016/j.ejmech.2017.09.044 | doi-access = free }} 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.{{cite journal | vauthors = Patel D, Bauman JD, Arnold E | title = Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery | journal = Progress in Biophysics and Molecular Biology | volume = 116 | issue = 2–3 | pages = 92–100 | date = Aug 2014 | pmid = 25117499 | doi = 10.1016/j.pbiomolbio.2014.08.004 | pmc = 4501029 | doi-access = free }}

Once a fragment (or a combination of fragments) have been identified, protein X-ray crystallography is used to obtain structural models of the protein-{{Not a typo|fragment(s)}} complexes.{{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 }}{{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 | pmc=3497300| doi-access = free }} Such information can then be used to guide organic synthesis for high-affinity protein ligands and enzyme inhibitors.{{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 }}

Advantages of screening low molecular weight fragment based libraries over traditional higher molecular weight chemical libraries are several.{{cite journal | vauthors = Erlanson DA, McDowell RS, O'Brien T | s2cid = 15138472 | 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 }} 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.

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

{{Reflist}}

{{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 | 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 | isbn = 978-0-12-381274-2 }}
• {{cite book | author = Erlanson DA | title = Fragment-Based Drug Discovery and X-Ray Crystallography | chapter = Introduction to Fragment-Based Drug Discovery | journal = Top Curr Chem | volume = 317| 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}}

Category:Drug discovery

Category:Biotechnology