Doctoral defence: Tõnis Laasfeld “Integrating Image Analysis and Quantitative Modeling for a Holistic view of GPCR Ligand Binding Dynamics”

On 29 August at 14:15 Tõnis Laasfeld will defend his doctoral thesis “Integrating Image Analysis and Quantitative Modeling for a Holistic view of GPCR Ligand Binding Dynamics”  for obtaining the degree of Doctor of Philosophy (in Chemistry).

Supervisors:

 Professor of Bioorganic Chemistry Ago Rinken, University of Tartu

 Associate Professor in Bioinformatics Leopold Parts, University of Tartu

Opponent:

Professor Martin Lohse, ISAR Bioscience GmbH (Germany)

Summary

Presumably, the idiom "to swallow a bitter pill" has emerged from the fact that many medicines have a bitter taste. However, many drugs have more serious side effects, and there is no cure for a number of diseases. Various scientific disciplines contribute to the development of drugs and the improvement of existing ones. The purpose of a drug is to modify receptor-controlled processes in the body to achieve a therapeutic or symptom-relieving effect. One of the most important targets of drugs are thr G-protein-coupled receptors. In humans, there are nearly 800 different G-protein-coupled receptors that regulate various functions such as vision and heart function. So far, it has not been possible to fully decipher all the intricacies of receptor systems. In this doctoral thesis, experimental systems based on spectroscopy and microscopy were developed to monitor the binding of drug molecules to receptors in lipid nanoparticles and living cells. For example, using total internal reflection microscopy, the binding of individual fluorescent drug molecules to receptors on the surface of nanoparticles could be observed. Since these methods produce vast amounts of data, the Aparecium Software, together with deep learning models, was created to extract essential information from this data set. By using the data from experimental systems, kinetic models were developed that can dynamically describe and predict the binding of drugs to receptors. For instance, it was discovered that muscarinic M2 acetylcholine receptors are mostly located in the membranes as dimers, and once one drug molecule binds to one receptor monomer, it locks the other drug molecule onto the first one. With this knowledge, it would be possible to design drugs with longer therapeutic effect or design drugs with entirely new properties. In the future, the developed models and methods could be used to screen a large numbers of molecules and identify those that possess these interesting properties.

Defence can be also followed in Teamsis.