Synthetically accessible de novo design using reaction vectors: Application to PARP1 inhibitors.

Autor: Ghiandoni GM; Information School, University of Sheffield, Regent Court, 211 Portobello, Sheffield, S1 4DP, UK., Flanagan SR; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK., Bodkin MJ; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK., Nizi MG; Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy., Galera-Prat A; Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland., Brai A; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy., Chen B; Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield, S3 7HF, UK., Wallace JEA; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK., Hristozov D; Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK., Webster J; Information School, University of Sheffield, Regent Court, 211 Portobello, Sheffield, S1 4DP, UK., Manfroni G; Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy., Lehtiö L; Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland., Tabarrini O; Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy., Gillet VJ; Information School, University of Sheffield, Regent Court, 211 Portobello, Sheffield, S1 4DP, UK.
Jazyk: angličtina
Zdroj: Molecular informatics [Mol Inform] 2024 Apr; Vol. 43 (4), pp. e202300183. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1002/minf.202300183
Abstrakt: 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 of 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.
(© 2024 The Authors. Molecular Informatics published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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