Fragment-based drug discovery: opportunities for organic synthesis

Abstract

Herein is described the concept of fragment sociability and the opportunities for organic chemistry to address the challenges of fragment elaboration.

Emergent synthetic methods for the modular advancement of sp3-rich fragments

“…Moving forwards, practitioners of fragment-based drug discovery will signicantly benet from the development of robust methods that resolve such challenges. Nonetheless the state-of-the-art hints at a bright future for both mission-driven 14,15,30 and 'blue skies' methodology development for sp 3 -rich fragment-to-lead optimisation.…”

“…3 showcases potential instances where the methods discussed could prove to be useful as synthetic tools for fragment-to-lead development. A limitation of this exercise is that it is likely that there are sp 3 -rich fragment hits that were not previously developed into leads due to the confines of the available methodologies for fragment elaboration at the time of hit discovery, 30 but such hits might now be developable using methodologies highlighted in this manuscript.…”

“…[26][27][28][29] However, in the absence of functionalisable synthetic handles, concerns may arise about the direct synthetic developability of sp 3 -rich fragments due to a lack of predictable synthetic methods to aid their advancement. 30 Indeed, pre-emptive development and exemplication of synthetic chemistries for direct fragment elaboration has recently been framed as a pressing challenge for the synthetic chemistry community. 15,30 While sp 3 -rich fragments pose challenges with regards to their synthetic (and biological) advancement, they also offer exciting opportunities for the development of new synthetic methods.…”

“…30 Indeed, pre-emptive development and exemplication of synthetic chemistries for direct fragment elaboration has recently been framed as a pressing challenge for the synthetic chemistry community. 15,30 While sp 3 -rich fragments pose challenges with regards to their synthetic (and biological) advancement, they also offer exciting opportunities for the development of new synthetic methods. 14,15,24,[30][31][32][33] This review highlights recent enabling synthetic methods that are likely to be useful towards the advancement of sp 3 -rich fragment hits into higher affinity lead and drug compounds.…”

C–H functionalisation tolerant to polar groups could transform fragment-based drug discovery (FBDD)

“…In our experience, we have encountered several in-house cases of fragment-to-lead (F2L) elaboration that have proven problematic as the protein architecture necessitated growth from C(sp 2 ) and C(sp 3 ) atoms originating on the fragment and these modifications were required in the presence of the fragment's polar functionality, which is required for binding. 13 To examine how universal this challenge is to FBDD, we sought to investigate recent accounts of F2L campaigns reported in literature, and the findings of this analysis are reported herein. It is important to note that as this analysis is based on published examples of successful F2L programs, it could be skewed by a ‘survivorship bias’.…”