Gillet, V. orcid.org/0000-0002-8403-3111, Ghiandoni, G.M., Flanagan, S. et al. (11 more authors) (2024) Synthetically accessible de novo design using reaction vectors: application to PARP1 inhibitors. Molecular Informatics, 43 (4). e202300183. ISSN 1868-1743
Abstract
De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction-based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand-coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction-based de novo design to the design of synthetically accessible and biologically active compounds as proof-of-concept or our reaction vector-based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. Molecular Informatics published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | de novo drug design; reaction informatics; synthetic accessibility |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Social Sciences (Sheffield) > Information School (Sheffield) |
Funding Information: | Funder Grant number Biotechnology and Biological Sciences Research Council BB/R505821/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Jan 2024 17:15 |
Last Modified: | 07 Nov 2024 12:02 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/minf.202300183 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:208253 |