Machine learning to predict metabolic drug interactions related to cytochrome P450 isozymes

Ning Ning Wang, Xiang Gui Wang, Guo Li Xiong, Zi Yi Yang, Ai Ping Lu, Xiang Chen, Shao Liu*, Ting Jun Hou*, Dong Sheng Cao*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

14 Citations (Scopus)


Drug–drug interaction (DDI) often causes serious adverse reactions and thus results in inestimable economic and social loss. Currently, comprehensive DDI evaluation has become a major challenge in pharmaceutical research due to the time-consuming and costly process of the experimental assessment and it is of high necessity to develop effective in silico methods to predict and evaluate DDIs accurately and efficiently. In this study, based on a large number of substrates and inhibitors related to five important CYP450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), a series of high-performance predictive models for metabolic DDIs were constructed by two machine learning methods (random forest and XGBoost) and 4 different types of descriptors (MOE_2D, CATS, ECFP4 and MACCS). To reduce the uncertainty of individual models, the consensus method was applied to yield more reliable predictions. A series of evaluations illustrated that the consensus models were more reliable and robust for the DDI predictions of new drug combination. For the internal validation, the whole prediction accuracy and AUC value of the DDI models were around 0.8 and 0.9, respectively. When it was applied to the external datasets, the model accuracy was 0.793 and 0.795 for multi-level validation and external validation, respectively. Furthermore, we also compared our model with some recently published tools and then applied the final model to predict FDA-approved drugs and proposed 54,013 possible drug pairs with potential DDIs. In summary, we developed a powerful DDI predictive model from the perspective of the CYP450 enzyme family and it will help a lot in the future drug development and clinical pharmacy research.

Original languageEnglish
Article number23
Number of pages16
JournalJournal of Cheminformatics
Issue number1
Publication statusPublished - 15 Apr 2022

Scopus Subject Areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Computer Graphics and Computer-Aided Design
  • Library and Information Sciences

User-Defined Keywords

  • Adverse drug reactions
  • CYP450
  • Drug combination
  • Machine learning
  • Metabolic drug interaction


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