Targeting Schizont Egress Antigen-1 in Infected Red Blood Cells: Docking-Based Fingerprinting, Density Functional Theory, Molecular Dynamics Simulations, and Binding Free Energy Analysis.

Malaria remains a global health crisis, with the World Health Organization (WHO) reporting 241 million cases and 627,000 deaths worldwide in 2020, predominantly affecting Sub-Saharan Africa. The region accounted for 95% of cases and 96% of deaths, reflecting the immense challenges in malaria prevention and treatment. Schizont Egress Antigen-1 (PfSEA-1) is crucial in facilitating immune evasion and promoting the sequestration of infected red blood cells (RBCs), contributing to severe malaria symptoms, including cerebral malaria, and necessitates the urgent identification of novel or repurposed drugs targeting PfSEA1. The protein structure of PfSEA-1 (UniProt ID: A0A143ZXM2) was modelled in three dimensions, prepared, and subjected to a 50 ns molecular dynamics (MD) simulation to achieve a stable structure. The equilibrated structure was minimised for molecular docking against the DrugBank compound library. Docking analysis identified potential inhibitors, including Alparabinos, Dihycid, Ambenzyne, Amiflupipquamine, Ametchomine, and Chlobenethyzenol, with docking scores ranging from -8.107 to -4.481 kcal/mol. Advanced analyses such as interaction fingerprints, density functional theory (DFT), and pharmacokinetics evaluations were conducted. Finally, a 100 ns MD simulation in the NPT ensemble was performed to assess the stability of protein-ligand complexes, with binding free energy and total energy calculations derived from the simulation trajectories. The identified compounds exhibited satisfactory pharmacokinetic profiles and binding interactions with PfSEA-1. The MD simulations demonstrated overall stability, with minor fluctuations in some instances. Key intermolecular interactions were observed, supporting the binding stability of the identified compounds. Binding free energy calculations confirmed favourable interactions, underscoring their potential as therapeutic agents against Plasmodium falciparum. While the in silico results are promising, experimental validation is essential to confirm their efficacy and safety for clinical use. These findings highlight PfSEA-1 as a promising antimalarial target and identify potential inhibitors with strong binding affinities and favourable pharmacokinetics. While the computational results are encouraging, further in vitro and in vivo validation is necessary to confirm their therapeutic potential and facilitate future drug development.