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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
Fragment-based discovery aiming at a novel modulation of malate
dehydrogenase and beyond

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.