Plasmodium falciparum is main causative agent of malaria, a disease that affects half of world’s population. The parasite’s dependence on glycolysis makes this pathway a suitable target for drug development. Understanding the structure-function dynamics of glycolytic enzymes in different species has an important impact on the development of selective drug analogues. Parasitic resistance and drug side effects of current antimalarial drugs have complicated and increased the cost of curing malaria.Molecular docking was used to explore structural motifs responsible for the interactions between triose phosphate isomerase (TIM) from Plasmodium falciparum (PFTIM) and human (HTIM) tissues. Fourteen antimalarial drugs were examined. The binding affinities and domains identified serve as a basis for modeling novel analogues.For all drugs modeled, PFTIM complexes displayed stronger binding affinities compared to HTIM. A dissociation constant (KI) of 40.2 mM was obtained for the interaction between primaquine and HTIM and 1.22 mM with PFTIM. This represents a 33-fold increase in selective binding to PFTM compared to HTIM. Mefloquine shows a 24-fold increase, and one new test ligand showed 25-fold increase in binding.The dimer interface and other pocket close to the active site are the main pockets observed by the docking studies. Key residues at the dimer interphase (Y48, D49, V46, S45, E65, S211) form a tight pocket with favorable polar contacts. 75% of PFTIM ligand complexes preferred the dimer interphase suggesting a potential site for non-competitive inhibition. These data suggest that TIM is a candidate for development of antimalarial drugs.Faculty Sponsor: Dr. Neville Forlemu

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