Drug Designing against PfHT1 Coupled With Molecular Dynamics in Plasma Membrane Environment Reveals, Ligand-Induced...

Plasmodium falciparum hexose transporter 1 protein or PfHT1 is the major glucose transporter of the parasite and indispensable for its survival at the blood stage of infection. PfHT1 transports the hexose sugar to meet the energy demand of the parasite. Studying the mechanism of transport and designing structure specific inhibitors against PfHT1 is an intelligent strategy to kill malaria parasite by starving it out because at the blood stage the sole carbon source of Plasmodium falciparum is glucose. In this study the conformational dynamics of PfHT1 has been studied in detail in the apo and holo (inhibitor bound) form using Molecular Dynamics Simulation, which reveals that PfHT1 undergoes ligand induced closed state if compared with the apo form. The geometry of ligand binding pocket also shifts from the apo form in the presence of inhibitors. The lead molecules were obtained from screening nearly 4500 compounds. A de novo drug designing approach based on the skeleton of the leads, has produced inhibitors of PfHT1 with higher specificity and affinity. The drug screening data as well as the conformational dynamics study was validated using Molecular Dynamics Simulation. In simulation a near physiological environment was created for PfHT1 by constructing a lipid phase (phospholipid bilayer) sandwiched between aqueous phases (mimics extracellular and cytosolic polar environment).