O'Brien, Peter orcid.org/0000-0002-9966-1962, Downes, Thomas D, Jones, S Paul et al. (15 more authors) (2020) Design and Synthesis of 56 Shape Diverse 3-D Fragments. Chemistry : A European Journal. ISSN 1521-3765
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 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. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/N008332/1 EUROPEAN COMMISSION 675899 |
Depositing User: | Pure (York) |
Date Deposited: | 04 May 2020 15:20 |
Last Modified: | 08 Feb 2025 00:38 |
Published Version: | https://doi.org/10.1002/chem.202001123 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1002/chem.202001123 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160215 |