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 journalReview articlepeer-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 languageEnglish
Pages (from-to)2484-2496
JournalDrug discovery today
Volume27
Issue number9
Early online date23 Aug 2022
DOIs
Publication statusPublished - Sep 2022

Bibliographical note

© 2022 The Authors

Keywords

  • 3D
  • Fragment
  • Fragment-based drug discovery
  • Library
  • Synthesis

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