Prediction of the hERG Cardiotoxicity of Compounds Using Molecular Docking and Target-Specific Scoring Functions
MENG Jin-hui1, ZHANG Li1,2,3, WANG Lian-xin1, LIU Li-li1, LIU Miao1, LIU Hong-sheng2,3,4*
1. School of Life Science, Liaoning University, Shenyang 110036, China; 2. Liaoning Province Research Center for Computer Simulating and Information Processing of Bio-macromolecules, Shenyang 110036, China; 3. Technology Innovation Center for Computer Simulating and Information Processing of Bio-macromolecules of Shenyang, Shenyang 110036, China; 4. School of Pharmacy, Liaoning University, Shenyang 110036, China
Abstract：OBJECTIVE To develop a machine learning-based hERG(the human Ether-à-go-go-Related Gene) target-specific scoring function(RF-hERG-Score) to predict the inhibitory activity of drugs on hERG(pIC50). METHODS The random forest algorithm was used, and the structures of 1847 compound-hERG complexes generated by AutoDock Vina molecular docking and experimental binding affinity(pIC50) data were used as the training set. RESULTS In ten-fold cross-validation, RF-hERG-Score was more accurate than RF-Score(generic scoring function) and AutoDock Vina(empirical scoring function). Between the pIC50 predicted by RF-hERG-Score and the experimental pIC50, the Pearson correlation coefficient(Rp) was 0.603, the Spearman rank correlation coefficient(Rs) was 0.623, and the root mean square error(RMSE) was 0.849. In the two external test sets, the Rp, Rs, and RMSE of RF-hERG-Score were also higher than the other two methods and better than the prediction performance of the model reported in the corresponding research. CONCLUSION RF-hERG-Score improves the prediction accuracy of the binding affinity of hERG inhibitors and provides a new solution for using computational simulation methods to achieve accurate prediction of drug cardiotoxicity.
孟金蕙, 张力, 王廉馨, 刘黎黎, 刘苗, 刘宏生. 基于分子对接和靶标特异性打分函数的化合物hERG心脏毒性预测[J]. 中国药学杂志, 2022, 57(19): 1645-1650.
MENG Jin-hui, ZHANG Li, WANG Lian-xin, LIU Li-li, LIU Miao, LIU Hong-sheng. Prediction of the hERG Cardiotoxicity of Compounds Using Molecular Docking and Target-Specific Scoring Functions. Chinese Pharmaceutical Journal, 2022, 57(19): 1645-1650.
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