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

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 (PfGrp78) has been implicated as an ER stress response sensor. PfGrp78 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 PfGrp78, which can be potential inhibitors of PfGrp78. 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 PfGrp78 (β-SBD). The predicted binding site comprised the arch and pocket residues Gly⁴²⁶ to Thr⁴⁴⁶ and Pro⁴⁵⁵ to Val⁴⁵⁷, 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 PfGrp78 chaperone cycle. Taken together, our results predict preferential binding of the cyclodecapeptides to PfGrp78 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.