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. Molecular dynamics simulations revealed that the compounds, particularly SANC456, commonly induced considerable changes in the global conformation and dynamics of PfIleRS, suggesting potential allosteric modulatory effects. Importantly, all 11 SANC hits reduced the binding affinity of the nucleotide AMP molecule by at least 25%. Some SANC ligand-bound systems (SANC456, SANC1095, and SANC1104) significantly increased the distance between the AMP and Ile ligands. Possible explanations for these changes were explored using three dynamic residue network centrality metrics. Betweenness centrality identified a major allosteric pathway in holo PfIleRS spanning the entire protein length. In contrast, SANC382, SANC456, SANC522, SANC806 and SANC1095 ligand-bound systems exhibited delta BC pathways (SANC-protein minus holo-protein), induced by the ligands, extending from their respective pockets into the active site. Additionally, eigenvector centrality revealed two important residue clusters either side of the holo active site which became altered in the ligand-bound systems, indicating possible allosteric activity. Lastly, many SANC systems showed decreased closeness centrality of zinc finger and active site residues, including the HYGH and KMSKR motifs. We believe that the compounds identified in this study as potential allosteric inhibitors have strong translational potential and warrant further investigation through in vitro and in vivo experiments. Overall, they hold promise as starting points for the development of new and effective antimalarial therapies, particularly against multidrug-resistant Plasmodium parasites.