Allosteric modulation of Plasmodium falciparum Isoleucyl tRNA synthetase by South African natural compounds.

Targeting Plasmodium falciparum (Pf) aminoacyl tRNA synthetases is a viable strategy to overcome malaria parasite multi-drug resistance. Here, we focused on Pf Isoleucyl tRNA synthetase (PfIleRS) to identify potential allosteric inhibitors from 1019 South African Natural Compounds (SANC). Eleven potential hits, which passed ADMET and PAINS, were selected based on their docking binding affinity which was higher for PfIleRS than for human IleRS.

Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin.

Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and in vitro antiplasmodial validation of Mitomycin (MMC) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis.