Abstract
Malaria remains a significant global health challenge, with emerging resistance to current treatments necessitating the development of novel therapeutic strategies. P. falciparum Glutathione Reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarial drugs and dual drugs combining aminoquinoline derivatives with GR inhibitors using molecular docking and molecular dynamics simulations. Our findings reveal promising interactions between PfGR and antimalarial drugs, with the naphthoquinone Atovaquone (ATV) demonstrating particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity compared to reference inhibitors, suggesting their efficacy in inhibiting PfGR. Insights into their interaction mechanisms and structural dynamics are described. Overall, this research provides valuable insights into the potential of targeting PfGR and encourages further exploration of its role in the mechanisms of action of antimalarial drugs, including dual drugs, to enhance antiparasitic efficacy.