Gong_2021_Mol.Divers__

Dipeptidyl peptidase-4 (DPP4) is highly participated in regulating diabetes mellitus (DM), and inhibitors of DPP4 may act as potential DM drugs. Therefore, we performed a novel artificial intelligence (AI) protocol to screen and validate the potential inhibitors from Traditional Chinese Medicine Database. The potent top 10 compounds were selected as candidates by Dock Score. In order to further screen the candidates, we used numbers of machine learning regression models containing support vector machines, bagging, random forest and other regression algorithms, as well as deep neural network models to predict the activity of the candidates. In addition, as a traditional method, 2D QSAR (multiple linear regression) and 3D QSAR methods are also applied. The AI methods got a better performance than the traditional 2D QSAR method. Moreover, we also built a framework composed of deep neural networks and transformer to predict the binding affinity of candidates and DPP4. Artificial intelligence methods and QSAR models illustrated the compound, 2007_4105, was a potent inhibitor. The 2007_4105 compound was finally validated by molecular dynamics simulations. Combining all the models and algorithms constructed and the results, Hypecoum leptocarpum might be a potential and effective medicine herb for the treatment of DM.