Search for novel Plasmodium falciparum PfATP4 inhibitors from the MMV Pandemic Response Box through a virtual screening approach

• Published in: Journal of biomolecular structure & dynamics 2024-08, Vol.42 (12), p.6200-6211
• Main Authors: Reghunandanan, Keerthy, T P, Akhila, Krishnan, Nandini, K M, Darsana, Prasad, Roshny, Nelson-Sathi, Shijulal, Chandramohanadas, Rajesh
• Format: Article
• Language: English
• Subjects: Anti-malarials; drug discovery; molecular docking; molecular dynamic simulations; Pandemic Response Box; PfATP4
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2232459

Owing to its life cycle involving multiple hosts and species-specific biological complexities, a vaccine against Plasmodium, the causative agent of Malaria 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 Malaria since the best drug available to-date; Artemisinin and its combinations are also rapidly losing efficacy. Sodium ATPase (PfATP4) of Plasmodium has been recently explored as a suitable target for new antimalarials such as Cipargamin. Prior studies showed that multiple compounds from the Medicines for Malaria Venture (MMV) chemical libraries were efficient PfATP4 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 PfATP4 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 Malaria through abrogation of PfATP4 activity. Communicated by Ramaswamy H. Sarma