Structural Analysis of the Interaction of Pyrazole and Benzimidazole Core Compounds with PfATP4.

P-type cation ATPase in Plasmodium falciparum(PfATP4) serves as one of the important emerging drug targets for the treatment of the malaria. PfATP4 maintains sodium homeostasis in the parasite and its inhibition causes the death of the parasite through a mechanism that mimics premature schizogony. Over the past few years, we and others have identified ~20 different chemotypes of molecules that can disrupt sodium homeostasis via PfATP4. We have developed two series of potent PfATP4 inhibitors with a pyrazole and/or benzimidazole core and tested them on wild type and lab resistant strains of P. falciparum. However, due to lack of PfATP4 crystal structure, we have limited understanding of the structure-activity relationship among the analogs of these molecules and the mechanism of inhibition of PfATP4 which has hindered the rational optimization of the discovered inhibitors. In this study, we modeled the E1 and E2 states of PfATP4 using homology modeling with the corresponding state templates from the mammalian Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA). Models of PfATP4 were refined using molecular dynamics simulations and ~200 pyrazole and benzimidazole compounds were docked to the binding site using GOLD molecular docking software. Results from the docking study suggests that the compounds preferred mode of binding is to the proton bound E2 state of PfATP4. The docking scores significantly correlated with IC50 values with a correlation co-efficient > 0.7. Further MD simulations of the docked complexes suggested residues GLN172, GLN351, SER175 and ASN207 play a key role in ligand binding which may have a role in the development of resistance to PfATP4 inhibitors which needs further experimental validation.