In silico identification of selective cyclodecapeptide inhibitors targeting Plasmodium falciparum Grp78 chaperone

Abstract The increase in drug resistance by Plasmodium falciparum (Pf) remains a major challenge in eradicating malaria. The parasite drug resistance towards first line antimalarial therapy is associated with the parasite response to drug induced endoplasmic reticulum (ER) stress. The ER resident glucose-regulated protein 78 ( Pf Grp78) has been implicated as an ER stress response sensor. Pf Grp78 binds to stressed protein substrates to suppress their misfolding and increase the capacity of the parasite ER to maintain proteostasis for parasite survival under stress. However, there have been limited efforts to target the parasite ER protein folding system as a potential drug target. This study sought to identify peptides that mimic the substrates of Pf Grp78, which can be potential inhibitors of Pf Grp78. Using the chaperone-substrate relationship, we explored the mechanism of action of cyclodecapeptides, gramicidin S (GS) and tyrocidines (Trcs), which were previously shown to exhibit potent antimalarial activity. In this study, using molecular docking and molecular dynamics simulation predictions, we observed that cyclodecapeptides bind to a unique site, suggesting preferential binding towards the substrate binding domain of Pf Grp78 (β-SBD). The predicted binding site comprised the arch and pocket residues Gly 426 to Thr 446 and Pro 455 to Val 457 , respectively. Furthermore, our extensive thermodynamics simulations supported the stable binding of the peptides and unveiled distinct inhibitory mechanisms. Our analysis suggests that the anti-plasmodial cyclodecapeptides, TrcA and GS, are predicted to act by inducing conformational locking, which may restrict the dynamic flexibility essential for the Pf Grp78 chaperone cycle. Taken together, our results predict preferential binding of the cyclodecapeptides to Pf Grp78 over its parasite cytosolic isoform and the human homologs. This offers promise for more experimental validation towards defining the molecular mechanism of action of these compounds.