Potentials of Terpenoids as Inhibitors of Multiple Plasmodium falciparum Protein Drug Targets.

Purpose: The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments.

Method: In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies.

Results: From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation.

Conclusion: These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies.