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 among children. In this dissertation Atilio Reyes Romero researched the role of malate dehydrogenase protein at the biochemical level in the metabolism of the parasite and identified small molecules that bind at the oligomeric interface with an allosteric an inhibiting mechanism. This result paves the way for chemical optimisation to a new class of anti-malarial drugs with better selectivity than for the human isoforms. However, tackling protein interfaces, such as oligomeric interfaces, is an challenge in the discovery of medicines because they are flat with a dependency on a local network of molecular interactions spread over the surfaces. Natural and artificial macrocycles are a class of heterogeneous compounds that bind these interfaces. In This thesis will be Moloc, one of the first and most complete molecular modelling packages, presented. We have the accuracy, the diversity, the
the speed, completeness and efficiency of sampling in the production of macro-cyclicals.
We have quantified the results in accordance with four commercial software and four open access. The result is that Moloc is equivalent to or better than the proprietary products relating to the above metrics. These results imply that not only that Moloc can be used as an alternative to the design of macrocycles on the interface of proteins, but also the bioavailability of biologically relevant predict conformations (i.e. cell membranes that penetrate).