Structural Alerts and Random Forest Models in a Consensus Approach for Receptor Binding Molecular Initiating Events.
Russell, Paul J
Chemical research in toxicology
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Wedlake, A., Folia, M., Piechota, S., Allen, T., Goodman, J., Gutsell, S., & Russell, P. J. (2020). Structural Alerts and Random Forest Models in a Consensus Approach for Receptor Binding Molecular Initiating Events.. Chemical research in toxicology, 33 (2), 388-401. https://doi.org/10.1021/acs.chemrestox.9b00325
A molecular initiating event (MIE) is the gateway to an adverse outcome pathway (AOP), a sequence of events ending in an adverse effect. In silico predictions of MIEs are a vital tool in a modern, mechanism-focused approach to chemical risk assessment. For 90 biological targets representing important human MIEs, structural alert-based models have been constructed with an automated procedure that uses Bayesian statistics to iteratively select substructures. These models give impressive average performance statistics (an average of 92% correct predictions across targets), significantly improving on previous models. Random Forest models have been constructed from physicochemical features for the same targets, giving similarly impressive performance statistics (93% correct predictions). A key difference between the models is interpretation of predictions - the structural alert models are transparent and easy to interpret, whilst Random Forest models can only identify the most important physicochemical features for making predictions. The two complementary models have been combined in a consensus model, improving performance compared to each individual model (94% correct predictions) and increasing confidence in predictions. Variation in model performance has been explained by calculating a modelability index (MODI), using Tanimoto coefficient between Morgan fingerprints to identify nearest neighbor chemicals. This work is an important step towards building confidence in in silico tools for assessment of toxicity.
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External DOI: https://doi.org/10.1021/acs.chemrestox.9b00325
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300098
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