Search for novel <i>Plasmodium falciparum Pf</i>ATP4 inhibitors from the MMV Pandemic Response Box through a virtual screening approach

Owing to its life cycle involving multiple hosts and species-specific biological complexities, a vaccine against <i>Plasmodium</i>, the causative agent of <i>Malaria</i> remains elusive. This makes chemotherapy the only viable means to address the clinical manifestations and spread of this deadly disease. However, rapid surge in antimalarial resistance poses significant challenges to our efforts to eliminate <i>Malaria</i> since the best drug available to-date; Artemisinin and its combinations are also rapidly losing efficacy. Sodium ATPase (<i>Pf</i>ATP4) of <i>Plasmodium</i> has been recently explored as a suitable target for new antimalarials such as <i>Cipargamin</i>. Prior studies showed that multiple compounds from the Medicines for Malaria Venture (MMV) chemical libraries were efficient <i>Pf</i>ATP4 inhibitors. In this context, we undertook a structure- based virtual screening approach combined to Molecular Dynamic (MD) simulations to evaluate whether new molecules with binding affinity towards <i>Pf</i>ATP4 could be identified from the Pandemic Response Box (PRB), a 400-compound library of small molecules launched in 2019 by MMV. Our analysis identified new molecules from the PRB library that showed affinity for distinct binding sites including the previously known G358 site, several of which are clinically used anti-bacterial (MMV1634383, MMV1634402), antiviral (MMV010036, MMV394033) or antifungal (MMV1634494) agents. Therefore, this study highlights the possibility of exploiting PRB molecules against <i>Malaria</i> through abrogation of <i>Pf</i>ATP4 activity. Communicated by Ramaswamy H. Sarma