Identification of a novel binding mechanism of Quinoline based molecules with lactate dehydrogenase of Plasmodium falciparum

The deadliest disease caused by the Plasmodium species is malaria. Among other species, the infection caused by Plasmodium falciparum (Pf) is life-threatening. The biological function and three-dimensional structure of PfLDH and human LDH are very similar. Any treatment aiming to inhibit the PfLDH can also affect the activity of human LDH. This study aims to identify molecules that show high selectivity for PfLDH without having a profound effect on the activity of human LDH. In this study, 30 in-house synthesized Quinolines based molecules were docked with both PfLDH and human LDH. Based on molecular docking results, molecules 3j, 4b, 4h, 4m were showed selectivity towards PfLDH. All the four molecules had better binding affinity, ligand efficiency, lipophilic ligand efficiency, and torsion than Chloroquine (referenced inhibitor). Further, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations were carried out to validate the docking results and to compare the stability of selected complexes against the complex with Chloroquine. MD simulations showed stable dynamic behavior of all the selected molecules in comparison to Chloroquine. Finally, on the basis of MM-PBSA analysis, molecule 3j was revealed novel binding mechanism and was selected as the potent and selective inhibitor of PfLDH.Communicated by Ramaswamy H. Sarma.