Journal Article

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

Adegboyega, Abayomi Emmanuel, Igharo, Aiseosa Kingsley, Sani, Jamilu, Dauda, Garba, Iorjiim, Walter Mdekera, Jibril, Murtala Muhammad, Ogundele, Omobolanle Ibukun, Abiola, Okesola Mary, Adebisi, Iyabo Mobolawa, Johnson, Titilayo Omolara, Olorukooba, Amina Busola

2026

Overview

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. Graphical abstract

• Publisher: Springer Nature Singapore,Springer Nature B.V,Springer
• Subject: Affinity / Antiparasitic agents / Azadirachta indica / Binding sites / Bioavailability / Biochemistry / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Drug development / Drug resistance / Efflux / Environmental Chemistry / Fatalities / Flexibility / Geochemistry / Glucosides / Glycoproteins / Hemoglobin / Hydrogen bonds / Inhibitors / Ligands / Malaria / Molecular docking / Molecular dynamic simulations / Molecular dynamics / Parasites / Peptides / Phytochemicals / Plasmepsin II / Plasmodium falciparum / Proteases / Proteins / Simulation / Structural integrity / Toxicity