SAR by Space: Enriching Hit Sets from the Chemical Space
We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-b...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-08-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/24/17/3096 |
| _version_ | 1818475866551746560 |
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| author | Franca-Maria Klingler Marcus Gastreich Oleksandr O. Grygorenko Olena Savych Petro Borysko Anastasia Griniukova Kateryna E. Gubina Christian Lemmen Yurii S. Moroz |
| author_facet | Franca-Maria Klingler Marcus Gastreich Oleksandr O. Grygorenko Olena Savych Petro Borysko Anastasia Griniukova Kateryna E. Gubina Christian Lemmen Yurii S. Moroz |
| author_sort | Franca-Maria Klingler |
| collection | DOAJ |
| description | We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC<sub>50</sub> values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages. |
| first_indexed | 2024-12-10T09:18:09Z |
| format | Article |
| id | doaj.art-f9fd1d3cde3e4c9ca8fe4a49155cb0cc |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T09:18:09Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f9fd1d3cde3e4c9ca8fe4a49155cb0cc2022-12-22T01:54:47ZengMDPI AGMolecules1420-30492019-08-012417309610.3390/molecules24173096molecules24173096SAR by Space: Enriching Hit Sets from the Chemical SpaceFranca-Maria Klingler0Marcus Gastreich1Oleksandr O. Grygorenko2Olena Savych3Petro Borysko4Anastasia Griniukova5Kateryna E. Gubina6Christian Lemmen7Yurii S. Moroz8BioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, GermanyBioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, GermanyEnamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, UkraineEnamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, UkraineBienta/Enamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, UkraineBienta/Enamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, UkraineTaras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Kyiv, UkraineBioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, GermanyTaras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Kyiv, UkraineWe introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC<sub>50</sub> values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages.https://www.mdpi.com/1420-3049/24/17/3096chemical spacebromodomainsBRD4 inhibitorsnew chemical entities |
| spellingShingle | Franca-Maria Klingler Marcus Gastreich Oleksandr O. Grygorenko Olena Savych Petro Borysko Anastasia Griniukova Kateryna E. Gubina Christian Lemmen Yurii S. Moroz SAR by Space: Enriching Hit Sets from the Chemical Space Molecules chemical space bromodomains BRD4 inhibitors new chemical entities |
| title | SAR by Space: Enriching Hit Sets from the Chemical Space |
| title_full | SAR by Space: Enriching Hit Sets from the Chemical Space |
| title_fullStr | SAR by Space: Enriching Hit Sets from the Chemical Space |
| title_full_unstemmed | SAR by Space: Enriching Hit Sets from the Chemical Space |
| title_short | SAR by Space: Enriching Hit Sets from the Chemical Space |
| title_sort | sar by space enriching hit sets from the chemical space |
| topic | chemical space bromodomains BRD4 inhibitors new chemical entities |
| url | https://www.mdpi.com/1420-3049/24/17/3096 |
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