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Classification models and SAR analysis on HDAC1 inhibitors using machine learning methods

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Abstract

Histone deacetylase (HDAC) 1, a member of the histone deacetylases family, plays a pivotal role in various tumors. In this study, we collected 7313 human HDAC1 inhibitors with bioactivities to form a dataset. Then, the dataset was divided into a training set and a test set using two splitting methods: (1) Kohonen’s self-organizing map and (2) random splitting. The molecular structures were represented by MACCS fingerprints, RDKit fingerprints, topological torsions fingerprints and ECFP4 fingerprints. A total of 80 classification models were built by using five machine learning methods, including decision tree (DT), random forest, support vector machine, eXtreme Gradient Boosting and deep neural network. Model 15A_2 built by the XGBoost algorithm based on ECFP4 fingerprints showed the best performance, with an accuracy of 88.08% and an MCC value of 0.76 on the test set. Finally, we clustered the 7313 HDAC1 inhibitors into 31 subsets, and the substructural features in each subset were investigated. Moreover, using DT algorithm we analyzed the structure–activity relationship of HDAC1 inhibitors. It may conclude that some substructures have a significant effect on high activity, such as N-(2-amino-phenyl)-benzamide, benzimidazole, AR-42 analogues, hydroxamic acid with a middle chain alkyl and 4-aryl imidazole with a midchain of alkyl whose α carbon is chiral.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21675010), and “Chemical Grid Project” of Beijing University of Chemical Technology. We thank Molecular Networks GmbH, Erlangen, Germany for providing the programs CORINA Symphony.

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Authors and Affiliations

  1. State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, China

    Rourou Li, Yujia Tian, Zhenwu Yang, Yueshan Ji & Aixia Yan

  2. School of International Education, Beijing University of Chemical Technology, Beijing, China

    Jiaqi Ding

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  1. Rourou Li
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Li, R., Tian, Y., Yang, Z. et al. Classification models and SAR analysis on HDAC1 inhibitors using machine learning methods. Mol Divers 27, 1037–1051 (2023). https://doi.org/10.1007/s11030-022-10466-w

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