In Silico Identification of Toddalia asiatica‐Derived Multi‐Target Antimalarial Leads Against PfAP2‐I‐TF, EACPR, and PfTopoVIB

Plasmodium (P) falciparum accounts for over 90% of malaria‐related deaths globally. Existing antimalarial drugs are increasingly associated with pathogen resistance, highlighting the urgent need for safer and more effective alternatives. In this study, three essential target proteins—PfAP2‐I‐TF (involved in RBC digestion), EACPR (cell membrane synthesis), and PfTopoVIB (DNA replication)—were selected due to limited prior drug exploration. Thirteen phytocompounds from Toddalia asiatica were screened through PubChem, yielding 576 similar molecules for docking studies using AutoDock. Among these, compound AKOS017940783 showed the best docking scores (−7.5, −8.5, and −6.5 kcal/mol) and formed 4, 3, and 2 hydrogen bonds with PfAP2‐I‐TF, EACPR, and PfTopoVIB, respectively. In contrast, standard drugs (chloroquine, triclosan, and primaquine) had lower docking scores (−7.2, −8.3, and −6.1 kcal/mol) and fewer interactions (0, 0, and 1 bond). Subsequent drug‐likeness and ADMET profiling confirmed the compound's safety. A 300 ns molecular dynamics simulation revealed enhanced structural stability of AKOS017940783 with all three targets compared to standard drugs. Based on its strong binding affinity, favorable pharmacokinetic profile, and stable protein‐ligand interactions, AKOS017940783 emerges as a promising lead for further in vitro validation as a novel antimalarial candidate against P. falciparum .