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Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion
Authors:
Sarah L.
Kidd
(University of Cambridge)
,
Elaine
Fowler
(University of Cambridge)
,
Till
Reinhardt
(University of Cambridge)
,
Thomas
Compton
(University of Cambridge)
,
Natalia
Mateu
(University of Cambridge)
,
Hector
Newman
(University of Warwick; Diamond Light Source)
,
Dom
Bellini
(University of Warwick)
,
Romain
Talon
(Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford)
,
Joseph
Mcloughlin
(University of Cambridge)
,
Tobias
Krojer
(Target Discovery Institute, University of Oxford)
,
Anthony
Aimon
(Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford)
,
Anthony
Bradley
(Diamond Light Source)
,
Michael
Fairhead
(Structural Genomics Consortium (SGC), University of Oxford)
,
Paul
Brear
(University of Cambridge)
,
Laura
Diaz-saez
(Target Discovery Institute; Structural Genomics Consortium (SGC), University of Oxford)
,
Katherine
Mcauley
(Diamond Light Source)
,
Hannah F.
Sore
(University of Cambridge)
,
Andrew
Madin
(AstraZeneca)
,
Daniel H.
O'donovan
(AstraZeneca)
,
Kilian
Huber
(Target Discovery Institute; Structural Genomics Consortium (SGC), University of Oxford)
,
Marko
Hyvonen
(University of Cambridge)
,
Frank
Von Delft
(Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford; University of Johannesburg)
,
Christopher G.
Dowson
(University of Warwick)
,
David R.
Spring
(University of Cambridge)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Chemical Science
State:
Published (Approved)
Published:
May 2020
Diamond Proposal Number(s):
18145
,
15649
,
14303
,
14493

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.
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Documents:
d0sc01232g.pdf