IDENTIFICATION OF NOVEL INHIBITORS OF PLASMODIUM PLASMEPSIN II FROM THE ZINC DATABASE USING A HIERARCHICAL VIRTUAL SCREENING APPROACH

Plasmodium falciparum plasmepsin II (PM II) is a key aspartic protease essential for hemoglobin degradation during the erythrocytic stage of the malaria parasite, making it an attractive drug target amid rising artemisinin resistance. This study utilized a hierarchical virtual screening (HVS) approach on the ZINC15 database to discover novel non-peptidic inhibitors. The workflow integrated ligand-based pharmacophore modeling (derived from known PM II inhibitors), structure-based high-throughput docking (AutoDock Vina against PDB ID: 1LF3), drug-likeness and ADMET filtering, and molecular dynamics (MD) simulations with MM-GBSA binding free energy calculations. From an initial library of over 1.2 million drug-like compounds, five top-ranked hits (ZINC compounds) exhibited docking scores ranging from -9.8 to -11.2 kcal/mol, outperforming the reference inhibitor pepstatin A (-8.7 kcal/mol). MD simulations (100 ns) confirmed complex stability (RMSD < 2.0 Å), persistent hydrogen bonds with the catalytic dyad (Asp34 and Asp214), and favorable MM-GBSA energies (-48 to -62 kcal/mol). These novel leads demonstrate drug-like properties and high binding affinity, providing a foundation for experimental validation and optimization as next-generation antimalarials. Keywords: plasmepsin II, hierarchical virtual screening, ZINC database, antimalarial drug discovery, molecular dynamics.