Identification of Novel High-Affinity Substrates of OCT1 Using Machine Learning-Guided Virtual Screening and Experimental Validation

• Published in: Journal of medicinal chemistry 2021-03, Vol.64 (5), p.2762-2776
• Main Authors: Jensen, Ole, Brockmöller, Jürgen, Dücker, Christof
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c02047

OCT1 is the most highly expressed cation transporter in the liver and affects pharmacokinetics and pharmacodynamics. Newly marketed drugs have previously been screened as potential OCT1 substrates and verified by virtual docking. Here, we used machine learning with transport experiment data to predict OCT1 substrates based on classic molecular descriptors, pharmacophore features, and extended-connectivity fingerprints and confirmed them by in vitro uptake experiments. We virtually screened a database of more than 1000 substances. Nineteen predicted substances were chosen for in vitro testing. Sixteen of the 19 newly tested substances (85%) were confirmed as, mostly strong, substrates, including edrophonium, fenpiverinium, ritodrine, and ractopamine. Even without a crystal structure of OCT1, machine learning algorithms predict substrates accurately and may contribute not only to a more focused screening in drug development but also to a better molecular understanding of OCT1 in general.