Targeting the Plasmodium falciparum plasmepsin V by ligand‐based virtual screening

• Published in: Chemical biology & drug design Vol. 93; no. 3; pp. 300 - 312
• Main Authors: Meissner, Kamila Anna, Kronenberger, Thales, Maltarollo, Vinícius Gonçalves, Trossini, Gustavo Henrique Goulart, Wrenger, Carsten
• Format: Journal Article
• Language: English
• Published: England 01-03-2019
• Subjects: Antimalarials - chemistry; Antimalarials - metabolism; Antimalarials - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Binding Sites; Catalytic Domain; Cell Survival - drug effects; Hep G2 Cells; Humans; Inhibitory Concentration 50; Ligands; Ligand‐based virtual screening; Molecular Docking Simulation; Organisms, Genetically Modified - metabolism; Plasmepsin V; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Plasmodium falciparum; Ligand-based virtual screening; Plasmepsin V
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13416

Malaria is a devastating disease depending only on chemotherapy as treatment. However, medication is losing efficacy, and therefore, there is an urgent need for the discovery of novel pharmaceutics. Recently, plasmepsin V, an aspartic protease anchored in the endoplasmaic reticulum, was demonstrated as responsible for the trafficking of parasite‐derived proteins to the erythrocytic surface and further validated as a drug target. In this sense, ligand‐based virtual screening has been applied to design inhibitors that target plasmepsin V of P. falciparum (PMV). After screening 5.5 million compounds, four novel plasmepsin inhibitors have been identified which were subsequently analyzed for the potency at the cellular level. Since PMV is membrane‐anchored, the verification in vivo by using transgenic PMV overexpressing P. falciparum cells has been performed in order to evaluate drug efficacy. Two lead compounds, revealing IC50 values were 44.2 and 19.1 μm, have been identified targeting plasmepsin V in vivo and do not significantly affect the cell viability of human cells up to 300 μm. We herein report the use of the consensus of individual virtual screening as a new technique to design new ligands, and we propose two new lead compounds as novel protease inhibitors to target malaria.
We report the use of the consensus of individual virtual screening to select new small molecules. Virtual screening of 5.5 million compounds using ligand‐based drug discovery resulted in to two lead compounds, revealing IC50 values on middle micromolar range on cell‐based assays, which do not significantly affect the cell viability of human cells. Transgenic P. falciparum parasites overexpressing PMV were employed to evaluate drug efficacy on a unique cell‐based assay system.