Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.



Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Author affiliations

Abstract

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

Graphical abstract: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Back to tab navigation

Supplementary files

Article information


Submitted
28 Feb 2020
Accepted
14 May 2020
First published
14 May 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

S. L. Kidd, E. Fowler, T. Reinhardt, T. Compton, N. Mateu, H. Newman, D. Bellini, R. Talon, J. McLoughlin, T. Krojer, A. Aimon, A. Bradley, M. Fairhead, P. Brear, L. Díaz-Sáez, K. McAuley, H. F. Sore, A. Madin, D. H. O'Donovan, K. V. M. Huber, M. Hyvönen, F. von Delft, C. G. Dowson and D. R. Spring, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC01232G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

Reproduced material should be attributed as follows:

  • For reproduction of material from NJC:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
  • For reproduction of material from PCCP:
    [Original citation] - Published by the PCCP Owner Societies.
  • For reproduction of material from PPS:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
  • For reproduction of material from all other RSC journals:
    [Original citation] - Published by The Royal Society of Chemistry.

Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.


Social activity

Search articles by author

Spotlight

Advertisements