Steroidal sapogenins as potential multi-target antimalarial agents: Computational insights into diosgenin and neotigogenin

Background: Drug resistance in Plasmodium falciparum continues to complicate malaria control and underscores the need to investigate new antimalarial candidates. Natural products provide structurally diverse compounds for drug discovery, yet the potential of steroidal sapogenins against multiple parasite protein targets remains insufficiently characterized. Comparative computational evaluation of related sapogenins may help identify promising structures for subsequent experimental investigation. Objective: This study comparatively evaluated the predicted binding of diosgenin and neotigogenin to five Plasmodium falciparum protein targets and assessed their predicted drug-likeness and pharmacokinetic properties. Methods: Molecular docking was performed against falcipain-2, plasmepsin II, P. falciparum enoyl-acyl carrier protein reductase (PfENR), cGMP-dependent protein kinase (PfPKG), and dihydrofolate reductase-thymidylate synthase (PfDHFR-TS). Docking protocols were evaluated by re-docking the corresponding crystallographic ligands, with root-mean-square deviation (RMSD) values used to assess pose reproduction. Predicted binding affinities and interaction profiles were compared, while SwissADME was used to estimate drug-likeness and selected pharmacokinetic properties Results: Predicted binding affinities ranged from -7.6 to -9.9 kcal/mol for diosgenin and from -8.2 to -9.4 kcal/mol for neotigogenin. Diosgenin produced the most favorable predicted scores against PfPKG (-9.9 kcal/mol) and PfENR (-9.8 kcal/mol), whereas neotigogenin showed a more favorable predicted score against plasmepsin II (-8.2 kcal/mol versus -7.6 kcal/mol for diosgenin). Re-docking RMSD values ranged from 1.4 to 1.8 Å. Both compounds were predicted to have high gastrointestinal absorption, although their relatively high lipophilicity warrants further assessment.. Conclusion: Diosgenin and neotigogenin showed favorable predicted binding to multiple P. falciparum protein targets, with differences in their relative binding scores across the target panel. These findings provide a preliminary basis for prioritizing the compounds for further antimalarial research. Enzyme inhibition assays, parasite-based studies, and experimental pharmacokinetic and safety assessments are required to determine whether the predicted interactions translate into biological activity. Novelty of the Study: To our knowledge, this is the first study that provides a comparative assessment of two structurally related steroidal sapogenins across five parasite protein targets, integrating docking validation, interaction profiling, and predicted pharmacokinetic characteristics within a single workflow.