Molecular Modelling Based Target Identification for Endo-Peroxides Class of Antimalarials

The emerging cases of artemisinin and endoperoxide drug resistance are becoming a challenge to antimalarial drug discovery and therapy. The exact mode of action of this class of antimalarials is still unknown which presents a bottleneck for the understanding of drug resistance as well as designing new lead molecules of this class. To address this issue, the molecular docking and scoring studies of a homogeneous and structurally diverse dataset of artemisinin derived trioxanes have been performed on each of the two plausible targets of this class viz. heme and PfATP6. Since the crystal structure of PfATP6 is unknown, its homology model was built utilizing the human SERCA1 protein crystallized structure as a template. The binding energies of the heme binding site of the docked artemisinin derivatives showed very good correlation with the antimalarial activity (r2 = 0.69), whereas the same study with the binding site of pfATP6 showed a very poor correlation (r2 = 0.12), suggesting heme to be the possible target of artemisinin derived endoperoxides.