Abstract
Mutations in ATP Binding Cassette (ABC)-transporter genes can have major effects on the bioavailability and toxicity of the drugs that are ABC-transporter substrates. Consequently, methods to predict if a drug is an ABC-transporter substrate are useful for drug development. Such methods traditionally relied on literature curated collections of ABC-transporter dependent membrane transfer assays. Here, we used a single large-scale dataset of 376 drugs with relative efficacy on an engineered yeast strain with all ABC-transporter genes deleted (ABC-16), to explore the relationship between a drug’s chemical structure and ABC-transporter substrate-likeness. We represented a drug’s chemical structure by an array of substructure keys and explored several machine learning methods to predict the drug’s efficacy in an ABC-16 yeast strain. Gradient-Boosted Random Forest models outperformed all other methods with an AUC of 0.723. We prospectively validated the model using new experimental data and found significant agreement with predictions. Our analysis expands the previously reported chemical substructures associated with ABC-transporter substrates and provides an alternative means to investigate ABC-transporter substrate-likeness.
Highlights
ATP Binding Cassette (ABC)-transporters are membrane proteins used for the transfer of a variety of substrates across the cell membranes (Dean et al, 2001; Locher, 2016)
Molecular ACCess System (MACCS) keys define a set of 166 chemical substructures that are often found in small molecule drugs (Durant et al, 2002)
For each of the 376 drugs used in the “green monster” study by Suzuki et al (2011), we generated MACCS-key binary profiles; each entry in the profile indicates if the corresponding substructure is found in the drug’s chemical structure
Summary
ATP Binding Cassette (ABC)-transporters are membrane proteins used for the transfer of a variety of substrates across the cell membranes (Dean et al, 2001; Locher, 2016). These proteins are intensively studied due to their importance in several diseases (Borst and Elferink, 2002). Mutations in the CFTR chloride channel, which is encoded by ABCC7 gene, result in abnormal solute transportation in lungs and cause cystic fibrosis in humans (Guggino and Stanton, 2006). Understanding both substrates and inhibitors of ABC-transporters is of extreme medical importance
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