Activity Prediction of Small Molecule Inhibitors for Antirheumatoid Arthritis Targets Based on Artificial Intelligence
Activity Prediction of Small Molecule Inhibitors for Antirheumatoid Arthritis Targets Based on Artificial Intelligence
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DOI：
10.1021/acscombsci.0c00169
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Zhang Yanmin
中科院分区：
文献类型：
--
作者：
Xing Guomeng;Liang Li;Deng Chenglong;Hua Yi;Chen Xingye;Yang Yan;Liu Haichun;Lu Tao;Chen Yadong;Zhang Yanmin
Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is compared to "immortal cancer" in industry. Currently, SYK, BTK, and JAK are the three major targets of protein tyrosine kinase for this disease. According to existing research, marketed and research drugs for RA are mostly based on single target, which limits their efficacy. Therefore, designing multitarget or dual-target inhibitors provide new insights for the treatment of RA regarding of the specific association between SYK, BTK, and JAK from two signal transduction pathways. In this study, machine learning (XGBoost, SVM) and deep learning (DNN) models were combined for the first time to build a powerful integrated model for SYK, BTK, and JAK. The predictive power of the integrated model was proved to be superior to that of a single classifier. In order to accurately assess the generalization ability of the integrated model, comprehensive similarity analysis was performed on the training and the test set, and the prediction accuracy of the integrated model was specifically analyzed under different similarity thresholds. External validation was conducted using single-target and dual-target inhibitors, respectively. Results showed that our model not only obtained a high recall rate (97%) in single-target prediction, but also achieved a favorable yield (54.4%) in dual-target prediction. Furthermore, by dustering dual-target inhibitors, the prediction performance of model in various dasses were proved, evaluating the applicability domain of the model in the dual-target drug screening. In summary, the integrated model proposed is promising to screen dual-target inhibitors of SYK/JAK or BTK/JAK as RA drugs, which is beneficial for the clinical treatment of rheumatoid arthritis.
