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

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 over-view 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) compu-tational design and synthesis (where 3D frag-ments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties). We conclude that a workflow that combines compu-tational 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.

Automated summary

This review discusses the synthetic strategies for preparing 3D fragments based on 25 papers published from 2011 to mid-May 2020, emphasizing diversity-oriented synthesis, scaffold synthesis and diversification, as well as computational design and synthesis. The conclusion suggests that a workflow combining computational design and other strategies, along with considerations of fragment properties and 3D shape, could promote the wider use of 3D fragments in fragment libraries and facilitate fragment-to-lead optimization.