Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries

Hanna F. Klein; David J. Hamilton; Iwan J.P. de Esch; Maikel Wijtmans; Peter O'Brien

doi:10.1016/j.drudis.2022.05.021

Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries

Hanna F. Klein
, David J. Hamilton
, Iwan J.P. de Esch
, Maikel Wijtmans
, Peter O'Brien^*

^*Corresponding author for this work

Research output: Contribution to Journal › Review article › Academic › peer-review

Abstract

In fragment-based drug discovery (FBDD), there is a developing appreciation that 3D fragments could offer opportunities that are not provided by 2D fragments. This review provides an overview of the synthetic strategies that have been used to prepare 3D fragments, as discussed in 25 papers published from 2011 to mid-May 2020. Three distinct strategies are highlighted: (i) diversity-oriented synthesis; (ii) the synthesis and diversification of scaffolds; and (iii) computational design and synthesis (where 3D fragments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties). We conclude that a workflow that combines computational design and one other strategy, together with a consideration of fragment properties, 3D shape and ‘fragment sociability’, could allow 3D fragments to feature more widely in fragment libraries and could facilitate fragment-to-lead optimisation.

Original language	English
Pages (from-to)	2484-2496
Number of pages	13
Journal	Drug Discovery Today
Volume	27
Issue number	9
Early online date	27 May 2022
DOIs	https://doi.org/10.1016/j.drudis.2022.05.021
Publication status	Published - Sept 2022

Bibliographical note

Funding Information:
We acknowledge funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028).

Funding Information:
We acknowledge funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028).

Publisher Copyright:
© 2022 The Authors

Funding

We acknowledge funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028). We acknowledge funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028).

Keywords

3D
Fragment
Fragment-based drug discovery
Library
Synthesis

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10.1016/j.drudis.2022.05.021

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title = "Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries",

abstract = "In fragment-based drug discovery (FBDD), there is a developing appreciation that 3D fragments could offer opportunities that are not provided by 2D fragments. This review provides an overview of the synthetic strategies that have been used to prepare 3D fragments, as discussed in 25 papers published from 2011 to mid-May 2020. Three distinct strategies are highlighted: (i) diversity-oriented synthesis; (ii) the synthesis and diversification of scaffolds; and (iii) computational design and synthesis (where 3D fragments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties). We conclude that a workflow that combines computational design and one other strategy, together with a consideration of fragment properties, 3D shape and {\textquoteleft}fragment sociability{\textquoteright}, could allow 3D fragments to feature more widely in fragment libraries and could facilitate fragment-to-lead optimisation.",

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note = "Funding Information: We acknowledge funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Sk{\l}odowska-Curie Actions programme (grant agreement number 675899; {\textquoteleft}Fragment-based drug discovery Network, FRAGNET{\textquoteright}), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; {\textquoteleft}Ready for growth: a new generation of highly versatile fragment libraries{\textquoteright}) and from The Royal Society (Industry Fellowship, INF\textbackslash{}R1\textbackslash{}191028). Funding Information: We acknowledge funding from the European Union{\textquoteright}s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Sk{\l}odowska-Curie Actions programme (grant agreement number 675899; {\textquoteleft}Fragment-based drug discovery Network, FRAGNET{\textquoteright}), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; {\textquoteleft}Ready for growth: a new generation of highly versatile fragment libraries{\textquoteright}) and from The Royal Society (Industry Fellowship, INF\textbackslash{}R1\textbackslash{}191028). Publisher Copyright: {\textcopyright} 2022 The Authors",

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language = "English",

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AU - Klein, Hanna F.

AU - Hamilton, David J.

AU - de Esch, Iwan J.P.

AU - Wijtmans, Maikel

AU - O'Brien, Peter

N1 - Funding Information: We acknowledge funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028). Funding Information: We acknowledge funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Actions programme (grant agreement number 675899; ‘Fragment-based drug discovery Network, FRAGNET’), from the Dutch Research Council under Applied and Engineering Sciences (grant number 18019; ‘Ready for growth: a new generation of highly versatile fragment libraries’) and from The Royal Society (Industry Fellowship, INF\R1\191028). Publisher Copyright: © 2022 The Authors

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N2 - In fragment-based drug discovery (FBDD), there is a developing appreciation that 3D fragments could offer opportunities that are not provided by 2D fragments. This review provides an overview of the synthetic strategies that have been used to prepare 3D fragments, as discussed in 25 papers published from 2011 to mid-May 2020. Three distinct strategies are highlighted: (i) diversity-oriented synthesis; (ii) the synthesis and diversification of scaffolds; and (iii) computational design and synthesis (where 3D fragments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties). We conclude that a workflow that combines computational design and one other strategy, together with a consideration of fragment properties, 3D shape and ‘fragment sociability’, could allow 3D fragments to feature more widely in fragment libraries and could facilitate fragment-to-lead optimisation.

AB - In fragment-based drug discovery (FBDD), there is a developing appreciation that 3D fragments could offer opportunities that are not provided by 2D fragments. This review provides an overview of the synthetic strategies that have been used to prepare 3D fragments, as discussed in 25 papers published from 2011 to mid-May 2020. Three distinct strategies are highlighted: (i) diversity-oriented synthesis; (ii) the synthesis and diversification of scaffolds; and (iii) computational design and synthesis (where 3D fragments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties). We conclude that a workflow that combines computational design and one other strategy, together with a consideration of fragment properties, 3D shape and ‘fragment sociability’, could allow 3D fragments to feature more widely in fragment libraries and could facilitate fragment-to-lead optimisation.

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Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries

Abstract

Bibliographical note

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Keywords

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