Insights from Molecular Dynamic Simulation Toward Molecular Mechanism of Mmv007571 to Exploit New Trend of Multitarget Inhibitors of Plasmodium Falciparum

MMV007571 and MMV020439 well known to inhibit New Permeability Pathway (NPP) function were recently investigated to also display a secondary profile of inhibition of enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) and cytochrome bc1 complex. Intricacies of their binding at the newly identified targets prompted us to study their binding using molecular docking and dynamics simulations approach. Interestingly, MD simulations revealed only MMV007571 illustrated notable binding characteristic as followed by known PfDHODH inhibitors to play role over the N-terminal domain leading to gate closing to inhibit entry of ubiquinone. Later on, pharmacophoric mapping was carried out to obtain a template of features possessed by MMV007571 required for multitarget inhibition. This pharmacophore map was then utilized to perform high throughput virtual screening against a large database to obtain a novel series of multitarget inhibitors which serve to combat drug resistant Plasmodium falciparum.