Design and Synthesis of 56 Shape Diverse 3-D Fragments

Peter O'Brien, Thomas D Downes, S Paul Jones, Hanna F Klein, Mary C Wheldon, Masakazu Atobe, Paul S Bond, James D Firth, Ngai S Chan, Laura Waddelove, Roderick E Hubbard, David C Blakemore, Claudia De Fusco, Stephen D Roughley, Lewis R Vidler, Maria Ann Whatton, Alison J-A Woolford, Gail L Wrigley

Research output: Contribution to journalArticlepeer-review


Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2-D molecules. Herein, we describe a workflow for the design and synthesis of 56 3-D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol -1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3-D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3-D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.

Original languageEnglish
Number of pages9
JournalChemistry : A European Journal
Early online date21 Apr 2020
Publication statusE-pub ahead of print - 21 Apr 2020

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