Molecular docking and dynamics identify novel high-affinity plasmepsin II inhibitors from neem phytochemicals for antimalarial drug development

Despite advances in ACTs, drug-resistant Plasmodium falciparum strains necessitates new therapeutics. While neem’s broad-spectrum bioactivity is well-known, our recent identification of host-plant synergies prompted this focused investigation into neem’s plasmepsin II inhibitors. This study explores Azadirachta indica (neem) phytochemicals as plasmepsin II (Plm-II) inhibitors—a key enzyme in the parasite’s hemoglobin degradation. Using molecular docking (PDB: 1LF3), pharmacophore modeling, induced fit docking (FID), and 100-ns molecular dynamic simulations (MDS), 320 neem compounds were screened, identifying five top candidates: Cerebroside C (highest affinity: -10.665 Kcal/mol, IFD: -14.785 Kcal/mol), Apigenin-7-O-β-D-glucoside, L-Epicatechin, (-)-Epigallocatechin, and Met-pent-carboxylate, all outperforming the standard ligand (-9.573 Kcal/mol). ADMET prediction revealed that while Cerebroside C exhibited the strongest Plm-II interactions (Tyr77/Asp214), it violated Lipinski’s rule and was a P-glycoprotein substrate, limiting bioavailability. In contrast, Apigenin-7-O-β-D-glucoside demonstrated optimal drug-likeness, solubility (-2.69 LogS), and no Pgp efflux. MD simulations further confirmed Apigenin-7-O-β-D-glucoside’s stability, with the Plm-II complex showing low RMSD (≤ 2.6 Å), RMSF (≤ 1.0 Å), 91% hydrogen bond occupancy, and sustained target interactions (Try77/Aps214) via hydrophobic contacts and hydrogen bonds, while radius of gyration (4.5 Å) and SASA analyses affirmed structural integrity. Cerebroside C demonstrates significant plasmepsin II inhibitory potential, while MD simulations establish Apigenin-7-O-β-D-glucoside as a stable Plm-II inhibitor with targeted interactions under dynamic conditions. Notably, the improved drug-likeness and absence of Pgp-mediated efflux of Apigenin-7-O-β-D-glucoside makes it a better pharmaceutically acceptable candidate over Cerebroside C regardless of the latter’s improved binding affinity.