Inhibiting the HGXPRT Enzyme in Plasmodium falciparum to Prevent Malaria

Plasmodium falciparum, the parasite responsible for the majority of deaths caused by malaria, requires purine to survive. These organisms are able to continually supply themselves with purine by processing hypoxanthine salvage from its host. Without the ability to create its own purine, the Plasmodium falciparum would die, which makes purine starvation a viable method of preventing deaths from malaria. The enzyme in the parasite that allows it to salvage purine is called the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme (HGXPRT). By inhibiting this enzyme with S-SerMe-ImmH phosphonate, the parasites will starve. Therefore, better binding affinity between the ligands and their respective binding sites on the enzyme increase the effectiveness of this antimalarial treatment. By using various computer-aided drug design software, primarily SeeSAR, the phosphonate ligands were adjusted to increase their binding affinity. Out of many attempted revisions, a small subset are substantially better than the original ligands. After using online bioactivity calculators, these improved ligands showed no signs of breaking any of Lipinski’s drug rules, nor did they become drastically more difficult to create in a lab. By making these changes to the phosphonate ligands, the S-SerMe-ImmH becomes an even more potent drug for inhibiting the HGXPRT enzyme in Plasmodium Falciparum, allowing more lives to be saved from malaria