Design and Synthesis of 56 Shape Diverse 3-D Fragments

TY - JOUR

T1 - Design and Synthesis of 56 Shape Diverse 3-D Fragments

AU - O'Brien, Peter

AU - Downes, Thomas D

AU - Jones, S Paul

AU - Klein, Hanna F

AU - Wheldon, Mary C

AU - Atobe, Masakazu

AU - Bond, Paul S

AU - Firth, James D

AU - Chan, Ngai S

AU - Waddelove, Laura

AU - Hubbard, Roderick E

AU - Blakemore, David C

AU - De Fusco, Claudia

AU - Roughley, Stephen D

AU - Vidler, Lewis R

AU - Whatton, Maria Ann

AU - Woolford, Alison J-A

AU - Wrigley, Gail L

N1 - © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2020/4/21

Y1 - 2020/4/21

N2 - 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.

AB - 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.

U2 - 10.1002/chem.202001123

DO - 10.1002/chem.202001123

M3 - Article

C2 - 32315100

SN - 0947-6539

JO - Chemistry : A European Journal

JF - Chemistry : A European Journal

ER -