Reprinted with permission from J. Chem. Inf. Model. 2019, 595, 1811-1825. Copyright 2018 American Chemical Society.
The project is designed as an interdisciplinary research approach, combining structure-based ligand discovery with biochemical in vitro studies. Structural models for three hepatocellular organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1) will be generated, and hepatocellular OATP-ligand interactions identified by a systematic large-scale docking study. Further, novel potential ligands of hepatocellular OATPs will be predicted in silico by virtual screening of large databases.
The human hepatic organic anion transporting polypetides (OATPs), termed OATP1B1, OATP1B3, and OATP2B1 are important for proper liver function because they mediate the uptake of a variety of substances into the liver. However, it is not known properly how the three different transporters work, their communalities and differences. Therefore, we want to understand how different molecules or drugs interact with the three different proteins on a molecular basis in order to learn about the driving forces for the binding and selectivity (preferred binding to one of the three). In the next step, this knowledge will be used to identify new molecules acting on one or several of the hepatic OATPs.
What are our Hypotheses?
- The three hepatic OATPs do possess communalities and differences regarding their protein structure.
- Those structural differences are influencing the way in which different molecules/drugs are recognized by the transporters, and thus their biological effects on the transporters might be different.
- Elucidating hepatic OATP-ligand interaction will therefore give insights into the molecular basis of how these transporters work and shed light on reasons for compound selectivity.
Which Methods do we use?
This project is designed as an interdisciplinary research approach, combining computational modelling of protein structures and compound-protein interactions with pharmacological testing of compound activity.
- Computer-generated structural models for the three hepatic OATPs (OATP1B1, OATP1B3, and OATP2B1) will be constructed on basis of other protein structures with a high degree of shape similarity.
- Interactions of the three hepatic OATPs with molecules/drugs will be identified by applying ‘ligand-protein docking’ of a large number of molecules, a method which computationally predicts the preferred orientation of a molecule when placed into a protein.
- Novel compounds potentially targeting OATPs will be predicted on basis of the computer models
- Experimental validation is done in the labs of Prof. Gergely Szakacs and Dr. Csilla Laczka.
What is new and special about this project?
Up to now, only very few computer-generated structural models are available for hepatic OATPs and no systematic large-scale docking study has been performed so far. In addition, our study for the first time compares the molecule-protein interactions between all three hepatic OATPs, and thus will give insights in reasons for compound selectivity. Moreover, our study will identify new hepatic OATP ligands which will serve for further functional characterization of the proteins. Moreover, knowledge about new drug-OATP interactions will help to increase the safety of medication schemes in clinics, because if one drug is blocking the transporter the other drug cannot be taken up into the liver anymore. This frequently causes severe side effects during drug therapy, which might be prevented by the findings of our study.
