Malaria continues to present great economic and disease burdens in tropical regions of the world. Plasmodium spp., the causative agent of malaria, kills 1-2 million people and infects an estimated 300-500 million people each year. Resistance to available malaria drugs contributes to the rising rates of mortality and morbidity. In light of the increasing resistance, it is rapidly becoming a major health priority to find new drugs that are effective, affordable, and safe. Our laboratory is focusing on a novel enzyme target for parasite drug design, protein farnesyltransferase (PFT), which catalyzes the addition of a 15-carbon isoprenoid lipid unit to the C-termini of a subset of proteins involved in cell cycle regulation and other vital functions. PFT inhibitors (PFTIs) have been extensively studied and developed by pharmaceutical companies as anti-cancer chemotherapeutic agents in humans. By adopting a “piggy-back” approach, many of these previously developed drugs can be used as starting points for finding Plasmodium specific PFTIs. Computer modeling was used to complement in vivo and in vitro drug studies in Plasmodium falciparum, comparing two novel classes of PFTIs. We started with the known crystal structure of a related compound in the mammalian PFT active site. Based on the relative affinities of the two novel PFTIs for the mammalian and Plasmodium PFTs, and the impact of an active site mutation in the Plasmodium PFT active site on these affinities, we predicted the binding modes of the two novel compounds in the PFT active site. This allowed us to predict variations in these compounds with the goals to improve PFTI activity, improve Plasmodium PFTI specificity, and deter the emergence of resistance.
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