The doctoral dissertation in the field of Molecular modelling will be examined at the Faculty of Health Sciences at Kuopio campus. The public examination will be streamed online.
What is the topic of your doctoral research? Why is it important to study the topic?
My doctoral research focuses on creating a diverse structural dataset for Organic Anion Transporting Polypeptides (OATPs), a crucial family of solute carrier transporters (SLCO). OATPs are vital for transporting a wide range of substances, including endogenous compounds, xenobiotics, and drugs, playing a critical role in drug absorption, distribution, and overall pharmacokinetics. Beyond their fundamental role in drug disposition, OATPs have been linked to severe diseases, including cancer, liver fibrosis, and cirrhosis, underscoring their clinical significance.
Despite their widespread distribution and importance, the structural basis and mechanisms underlying OATP-mediated substrate transport remain poorly understood. The aim of my thesis is to use advanced computational approaches such as molecular dynamics and MM-GBSA to unravel the complex mechanisms of OATP substrate transport and investigate their structural and mechanistic details. This research contributes to our understanding of drug transport through OATPs and lays the groundwork for improved therapeutic strategies.
What are the key findings or observations of your doctoral research?
We have generated the structural models of the OATPs and also predicted the binding poses of substrates to these models shedding light on the intricate mechanisms of substrate transport. One of our key findings was identifying the role of salt bridges among extracellular residues on transmembrane helices TM1, TM2, and TM7, which form an extracellular gate for substrate entry across all OATPs. These interactions are reported later in the cryo-EM structure (PDB ID: 8HNH) determined later, reinforcing the accuracy of our computational predictions. Additionally, these structural models were used to study the binding modes and transport mechanisms of neurosteroids via OATP1A2, resulting in valuable insights into the structure-activity relationships of neurosteroids with this transporter. Using the AlphaFold models of OATP1C1 we designed prodrugs based on thyroxine (T4) and 3,5-diiodo-L-tyrosine (DIT) to facilitate the delivery of anti-inflammatory drugs into glial cells. This research not only advances our understanding of OATP structure and function but also demonstrates the potential of computational models in guiding drug design and development.
What are the key research methods and materials used in your doctoral research?
The key methods employed in this dissertation are a combination of computational methods, including homology modelling, molecular docking, and molecular dynamics simulations, to explore the structural and functional dynamics of Organic Anion Transporting Polypeptides (OATPs). Homology models of all OATPs were developed in-house, complemented by the use of the AlphaFold model for OATP1C1. Molecular docking was then applied to predict the binding poses of various substrates to the OATP models, offering insights into potential interactions. To validate and refine these predictions, molecular dynamics simulations were conducted. These simulations provided a deeper understanding of the substrate binding events, capturing variability in binding poses and highlighting critical molecular interactions essential for substrate recognition and transport.
The doctoral dissertation of Arun Kumar Tonduru, MSc, entitled Computational exploration of OATP substrate binding and transport dynamics will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Thierry Langer of the University of Vienna, and the Custos will be Professor Antti Poso of the University of Eastern Finland. The public examination will be held in English.
