As opposed to drug metabolizing enzymes, the role of hepatic transporters in drug disposition/safety/efficacy is poorly understood. This is partly due to lack of selective transporter modulators (inhibitors/activators), preventing easy investigation of transporter-mediated drug clearance. Moreover, as some of these transporters were recently identified as pharmacological targets (e.g. NTCP for hepatitis B infection), their poorly characterized affinity profiles are hampering development of effective treatments. This project is aimed at identification of small molecules that potently and selectively modulate important drug transporters in the liver. Chemically diverse small molecule libraries will be explored for transporter modulation in cell lines transduced with a single human transporter. Subsequently, in silico models will be established for structure-based identification of new modulators through iteration. Selective transporter modulation by the most promising candidates will be confirmed with preclinical models of the liver (e.g. primary human hepatocytes, isolated perfused liver, mice with humanized liver). This project will yield: (i) selective modulators of hepatic transporters (useful for hepatic drug exposure modulation and during biopharmaceutical profiling of new drug candidates), (ii) small molecules interfering with hepatitis B virus infection, (iii) in silico models for structure-based identification of novel transporter modulators.