Abstract
Plasmodium falciparum Serine Hydroxymethyltransferase has never been used as target for antimalarial chemotherapy, possibly because its great sequence similarity with the human enzyme. This similarity suggests implies that P. falciparum may not be able to mutate this enzyme to develop resistance for chemotherapy. In this work, we have used differences on the dynamic behavior of the active sites of the crystallographic structure of the human enzyme and a homology model of parasite’s enzyme, both in complex with glycine, as N-glycine-[3-hydroxy-2-methyl-5phosphonooxymethyl-pyridin-4-yl-methane] and 5-formyl-6-hydrofolic acid, to design prototypes for selective inhibitors of this enzyme as new potential antimalarials. Those potential inhibitors are 5-formyl-6-hydrofolic acid derivatives with different charges and tail lengths. Molecular dynamics simulations and interaction energy estimates of the compounds within the active sites of both enzymes showed that compounds with a negative net charge and either shorter tails or longer amphoteric tails, would be more selective towards pfSHMT.
Highlights
Medicinal chemistry has undergone a revolutionary change in the last years
We tried a neutral and a negatively charged compound in physiologic conditions because dimeric forms of human Serine Hydroxymethyltransferase (hSHMT) and Plasmodium falciparum Serine Hydroxymethyltransferase (pfSHMT) are differently charged in physiologic conditions
A similar hypothesis has already been studied in a previous work where we proposed that a continuous positive potential region between the two active sites of the bifunctional enzyme Dihydrofolate Reductase-Tymidilate Synthase (DHFRTS) of P. falciparum, could be involved in an optimized mechanism for the transport of dihydrofolate negatively charged from TS active site to DHFR active site.[9]
Summary
Medicinal chemistry has undergone a revolutionary change in the last years. Rapid advances in biologicalMolecular Dynamics of the Interaction of Plasmodium falciparumJ. Medicinal chemistry has undergone a revolutionary change in the last years. Molecular Dynamics of the Interaction of Plasmodium falciparum. Mechanism of the target is, crucial to this approach. This target-oriented approach is know as “rational design of drugs” and involves many different stages, from choosing a suitable molecular target to marketing the final drug.[1] Along with target validation, the crucial step of this process is to find or design a compound that shows the desired pharmaceutical activity and selectivity on the target: the so-called “lead compound”. The level of activity may not be very significant and there may be undesirable side effects, but the lead compound provides a start for the process of drug development.[1]
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