Virtual screening of secondary metabolites from the African natural products database against Plasmodium falciparum : an integrated docking, MM-GBSA, and molecular dynamics study

An integrated pipeline combining QM ligand optimisation, docking, statistical enrichment, ADMET profiling, MM-GBSA rescoring and replicate MD simulations screened 443 secondary metabolites from the African Natural Products Database against 18 P. falciparum proteins. Docking validation (co-crystallized ligand RMSD 0.62–2.13 Å, median 1.35 Å) and benchmarking with chloroquine and artemisinin confirmed protocol reliability. Docking (GBVI/WSA dG ≤ −9 kcal/mol) produced 1130 hits, with class specific enrichment: flavonoids on PfAdSS, quinones on PfMyoA, terpenoids on PfDHODH. MM-GBSA rescoring of 191 priority complexes identified Stachannin A/PfDHODH (−106.50 kcal/mol) and 4-O-galloyl-gallotannin/PfDHFR-TS (−97.28 kcal/mol) as the strongest binders. Triplicate 200 ns MD simulations, extended to 1 µs for 4-O-galloyl-gallotannin/PfDHFR-TS and Jozimine A2/PfPNP, showed Jozimine A2 (IC₅₀ 1.4 nM) stably bound (Cα-RMSD 1.41 ± 0.16 Å; ligand RMSD ∼1.5 Å in two replicates, a stable alternative pose at ∼4.1 Å in the third, persistent for 1 µs) with key H-bonds to Cys208 and Tyr160. Stachannin A and 4-O-galloyl-gallotannin exhibited reproducible poses, while ceramide Liebrechtsianoside A retained occupancy but underwent tail-rotation reorganisation (ligand RMSD 13.5 ± 3.9 Å, ΔG_bind −49.5 ± 4.0 kcal/mol). PCA, free-energy landscapes and per-residue decomposition confirmed reproducibility. Four computational candidates emerge: Jozimine A2, Stachannin A, 4-O-galloyl-gallotannin and Albizia budmunchiamine alkaloids.