On 26 August at 10:15 Larisa Ivanovawill defend her thesis „Design of active compounds against neurodegenerative diseases” for obtaining the degree of Doctor of Philosophy (Molecular Technology).
Prof. Mati Karelson (PhD), UT Institute of Chemistry
Jaana Tammiku-Taul (PhD), UT Institute of Chemistry
Prof. Dan Lindholm (PhD, MD), University of Helsingi, Finland.
Today, neurodegenerative diseases are one of the most acute medical and social problems. This is due to both severe physical and mental disabilities resulting from the constant progression of the process, and the age-dependent nature of the vast majority of neurodegenerative diseases. The current accelerating increase in life expectancy inevitably leads to a significant increase in the number of such patients. There is currently no radical treatment for neurodegenerative disorders. One of the main obstacles to finding effective drugs is the length and cost of the process of developing a new drug. However, the development of modern molecular modelling and artificial intelligence methods has substantially shortened the time to dispense new medicines and reduced its cost.
This dissertation provides examples of the use of various methods of computer-aided drug design such as molecular docking and molecular dynamics to develop new potential candidates against neurodegenerative diseases. The high-throughput virtual screening of large molecular libraries enabled to identify effective compounds against target proteins against neurodegenerative diseases. In result, a series of natural compounds acting as inhibitors to enzymes related to different diseases was established. Notably, a fully novel compound acting against two proteins related to Alzheimer’s disease was predicted and experimentally verified.
One of the main causes of the neurodegeneration is the mostly age-related deficiency of so-called neurotrophic factors. Small molecules that can mimic the activity of these factors in cells would be thus very attractive novel drug candidates. In the present thesis, the computational modelling was used for detailed study of the mechanism of action of one of the most important neurotrophic factors (Glial cell-derived neurotrophic factor GDNF). The results of this study enabled to develop first time a compound that acted similarly to this factor itself. Whereas the experimentally measured activity of this compound was moderate, it creates a basis for the development of fully new type of drugs against Parkinson’s and Huntington’s diseases.