Machine Learning-Augmented Docking. 1. CYP inhibition prediction

13 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


A significant portion of the oxidative metabolism carried out by the human body is accomplished by six Cytochrome P450 (CYP) enzymes. The binding of small molecules to these enzymes affects drug activity and half-life. Additionally, the inhibition or induction of a CYP isoform by a drug can lead to drug-drug interactions, which in turn can lead to toxicity. In order to predict CYP inhibition, a variety of computational methods have been used, with docking methods being less accurate than machine learning (ML) methods. However, the latter learning methods are sensitive to training data and show reduced accuracy on test sets outside of the chemical space of the training set. In contrast, docking methods do not have this generalization issue and allow for visual analysis. We hypothesize that combining ML methods with docking can lead to improved results when predicting CYP inhibition. To test this hypothesis, we pair our in-house docking program FITTED with several ML techniques to investigate the accuracy and transferability of this hybrid methodology, which we term ML-augmented docking. We find that ML-augmented docking can significantly improve the accuracy of docking software while showing that using ligand features only provides similar accuracy. The generalisability of our docking and ligand-only ML models shows that the ML-augmented docking is modestly more generalizable than ligand machine learning.


CYP inhibition
Drug discovery
Computational method
Machine learning
Drug-drug interactions

Supplementary materials

Additional information
Additional information (input, PDB IDs) and graphs

Supplementary weblinks


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