An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors
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Wiley Open Access
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| Formato: | Artículo Open Access |
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Wiley
2024
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| author | Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu |
| author_facet | Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu |
| collection | Wiley Open Access |
| contents | An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu Protein Science AbstractThe identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CDK8‐focused screening library. The ensemble model consists of six different algorithms optimized for CDK8 inhibitor classification. The models were trained using a CDK8‐specific fragment library along with molecules containing CDK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CDK8‐focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CDK8‐focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CDK8 inhibitors, with one compound producing an IC50 value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CDK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CDK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CDK8. 10.1002/pro.5007 http://creativecommons.org/licenses/by/4.0/ |
| doi_str_mv | 10.1002/pro.5007 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_pro_5007 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu Protein Science An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors Tony Eight Lin Dyan Yen Wei‐Chun HuangFu Yi‐Wen Wu Jui‐Yi Hsu Shih‐Chung Yen Tzu‐Ying Sung Jui‐Hua Hsieh Shiow‐Lin Pan Chia‐Ron Yang Wei‐Jan Huang Kai‐Cheng Hsu Protein Science AbstractThe identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CDK8‐focused screening library. The ensemble model consists of six different algorithms optimized for CDK8 inhibitor classification. The models were trained using a CDK8‐specific fragment library along with molecules containing CDK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CDK8‐focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CDK8‐focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CDK8 inhibitors, with one compound producing an IC50 value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CDK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CDK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CDK8. 10.1002/pro.5007 http://creativecommons.org/licenses/by/4.0/ |
| title | An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors |
| topic | Protein Science |
| url | https://onlinelibrary.wiley.com/doi/10.1002/pro.5007 |