Computational Drug Repositioning for Targeting PfEMP1: Potential Therapeutics for Cerebral Malaria in Plasmodium falciparum.

Abstract

Cerebral malaria, a severe complication form of Plasmodium falciparum infection, remains a major global health challenge with limited treatment options. The National Programme currently recommends quinine- and artemisinin-based combination therapy (ACT) for the treatment of severe malaria. However, the growing resistance to these treatments highlights the urgent need for alternative therapeutic strategies. A key factor in cerebral malaria pathophysiology is P. falciparum erythrocyte membrane protein 1 (PfEMP1), which facilitates the sequestration of infected red blood cells in the microvasculature. Targeting PfEMP1 represents a promising approach for therapeutic interventions. This study uses a multi-modal computational approach to identify FDA-approved drugs that could be repurposed to target PfEMP1. Among the top candidate molecules are Lumacaftor, Vilazodone, Tucatinib, Lenvatinib, and Hydrocortisone Cypionate, which exhibit favorable docking energies (-9.1 to -8.3 kcal/mol) and potential oral bioavailability, as determined by receptor-based screening and absorbed, distributed, metabolized, and eliminated (ADME) analysis. Molecular dynamics simulations confirm stable interactions between these drug molecules and PfEMP1, supported by favorable potential energy profiles and structural stability. Additionally, protein-ligand interaction analysis identifies key residues involved in drug binding, providing insights into their molecular effectiveness. Gibbs's free energy landscape analysis further reinforces the stability of these drug-protein complexes, underscoring their potential as therapeutic agents. These findings highlight the significant role of computational approaches in drug discovery and offer valuable insights into repurposing FDA-approved drugs for cerebral malaria treatment.