Hepatocellular Organic Anion Transporting Polypeptides - OATP1B1, OATP1B3, and OATP2B1 - are transmembrane proteins located at the basolateral membranes of hepatocytes. They mediate endogenous compound uptake – such as bile salts and bilirubin - into hepatocytes, and are thus important for proper liver function. In addition, hepatic OATPs regulate the drug elimination process. Impairment of the function of hepatic OATPs is therefore associated with drug-drug interactions (DDIs), adverse drug effects, and liver toxicity. Understanding the structure-function relationship of hepatic OATPs and differences in their ligand profiles is crucial in order to avoid unwanted DDIs in the future. However, due to a lack of a crystal structure for OATPs, the promiscuous nature of these transporters, and a quite limited availability of reliable bioactivity data which is spread over different data sources in the open domain, these things are only insufficiently understood nowadays. To this end, we compiled ligand data for the three hepatic OATPs from various open data sources in a semi-automatic KNIME workflow. By fusing ligand bioactivity data from five different data sources (ChEMBL, UCSF-FDA TransPortal database, DrugBank, Metrabase, and IUPHAR) and annotating the data according to the measured endpoint and activity comment, we retrieved datasets for selective, dual-selective and pan-interacting substrates and inhibitors for OATP1B1, OATP1B3 and OATP2B1. Collected ligand datasets were further inspected for frequently occurring scaffolds and structural motifs, potentially responsible for selectivity towards specific hepatic OATPs. Insights gained on structural motifs likely conferring selectivity further served as a basis for building subtype-selective pharmacophore models. A screen of DrugBank identified several new compounds possessing novel scaffolds which are currently being tested for activity on all three transporters.

Data integration and fragment analysis reveal important structural motifs for ligand selectivity among hepatic organic anion transporting polypeptides

256th National Meeting (2018)

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