Virtual fragment screening for DNA repair inhibitors in vast chemical space
Abstract Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based doc...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56893-9 |
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| author | Andreas Luttens Duc Duy Vo Emma R. Scaletti Elisée Wiita Ingrid Almlöf Olov Wallner Jonathan Davies Sara Košenina Liuzhen Meng Maeve Long Oliver Mortusewicz Geoffrey Masuyer Flavio Ballante Maurice Michel Evert Homan Martin Scobie Christina Kalderén Ulrika Warpman Berglund Andrii V. Tarnovskiy Dmytro S. Radchenko Yurii S. Moroz Jan Kihlberg Pål Stenmark Thomas Helleday Jens Carlsson |
| author_facet | Andreas Luttens Duc Duy Vo Emma R. Scaletti Elisée Wiita Ingrid Almlöf Olov Wallner Jonathan Davies Sara Košenina Liuzhen Meng Maeve Long Oliver Mortusewicz Geoffrey Masuyer Flavio Ballante Maurice Michel Evert Homan Martin Scobie Christina Kalderén Ulrika Warpman Berglund Andrii V. Tarnovskiy Dmytro S. Radchenko Yurii S. Moroz Jan Kihlberg Pål Stenmark Thomas Helleday Jens Carlsson |
| author_sort | Andreas Luttens |
| collection | DOAJ |
| description | Abstract Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets. |
| format | Article |
| id | doaj-art-0365d4b6cf6f4cda854439e3e020c8a9 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0365d4b6cf6f4cda854439e3e020c8a92025-08-20T03:10:52ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56893-9Virtual fragment screening for DNA repair inhibitors in vast chemical spaceAndreas Luttens0Duc Duy Vo1Emma R. Scaletti2Elisée Wiita3Ingrid Almlöf4Olov Wallner5Jonathan Davies6Sara Košenina7Liuzhen Meng8Maeve Long9Oliver Mortusewicz10Geoffrey Masuyer11Flavio Ballante12Maurice Michel13Evert Homan14Martin Scobie15Christina Kalderén16Ulrika Warpman Berglund17Andrii V. Tarnovskiy18Dmytro S. Radchenko19Yurii S. Moroz20Jan Kihlberg21Pål Stenmark22Thomas Helleday23Jens Carlsson24Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMCScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMCDepartment of Biochemistry and Biophysics, Stockholm UniversityScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteDepartment of Biochemistry and Biophysics, Stockholm UniversityDepartment of Biochemistry and Biophysics, Stockholm UniversityScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteDepartment of Biochemistry and Biophysics, Stockholm UniversityScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMCScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteEnamine Ltd.Enamine Ltd.Enamine Ltd.Department of Chemistry-BMC, Uppsala UniversityDepartment of Biochemistry and Biophysics, Stockholm UniversityScience for Life Laboratory, Department of Oncology-Pathology, Karolinska InstituteScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMCAbstract Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets.https://doi.org/10.1038/s41467-025-56893-9 |
| spellingShingle | Andreas Luttens Duc Duy Vo Emma R. Scaletti Elisée Wiita Ingrid Almlöf Olov Wallner Jonathan Davies Sara Košenina Liuzhen Meng Maeve Long Oliver Mortusewicz Geoffrey Masuyer Flavio Ballante Maurice Michel Evert Homan Martin Scobie Christina Kalderén Ulrika Warpman Berglund Andrii V. Tarnovskiy Dmytro S. Radchenko Yurii S. Moroz Jan Kihlberg Pål Stenmark Thomas Helleday Jens Carlsson Virtual fragment screening for DNA repair inhibitors in vast chemical space Nature Communications |
| title | Virtual fragment screening for DNA repair inhibitors in vast chemical space |
| title_full | Virtual fragment screening for DNA repair inhibitors in vast chemical space |
| title_fullStr | Virtual fragment screening for DNA repair inhibitors in vast chemical space |
| title_full_unstemmed | Virtual fragment screening for DNA repair inhibitors in vast chemical space |
| title_short | Virtual fragment screening for DNA repair inhibitors in vast chemical space |
| title_sort | virtual fragment screening for dna repair inhibitors in vast chemical space |
| url | https://doi.org/10.1038/s41467-025-56893-9 |
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