Fragment-based discovery aiming at a novel modulation of malate dehydrogenase and beyond
|PhD ceremony:||Mr A. Reyes Romero|
|When:||January 11, 2021|
|Supervisors:||prof. dr. A.S.S. Dömling, prof. dr. T.A. Holak|
|Co-supervisor:||M.R. (Matthew) Groves, Prof|
|Where:||Academy building RUG|
|Faculty:||Science and Engineering|
Malaria is a disease caused by the parasite Plasmodium falciparum, which causes thousands of deaths especially among children. In this thesis, Atilio Reyes Romero investigated the role of malate dehydrogenase protein at the biochemical level in the parasite metabolism and identified small molecules that bind at the oligomeric interface with non-competitive mode of inhibition. These results pave the way for chemical optimization towards a new class of antimalarial drugs with better selectivity than human isoforms. However, addressing protein protein interfaces with conventional molecules and other proteins (i.e. antibodies) is challenging in drug discovery because they are flat with local network of molecular interactions spread across the surfaces. Natural and artificial macrocycles are a class of heterogeneous compounds that bind these interfaces. In this thesis, Moloc, one of the first and most complete molecular modeling packages, is presented. We have quantified the accuracy, diversity, speed, exhaustiveness and sampling efficiency in producing macrocycle conformations and we compared the results with four commercial software and four open access. As a result, Moloc was equivalent to or better than the proprietary products with respect to the above metrics. These results indicate not only that Moloc can be used as a tool to design macrocycles targeting oligomeric interfaces but could predict biologically relevant conformations (i.e. cell membranes permeating) and hence the bioavailability.