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

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria treatment relies on chemotherapy, but drug resistance is increasing.
• Plasmepsin V (PMV), a parasite protease, is crucial for malaria parasite survival and a validated drug target.

Purpose of the Study:

• To identify novel inhibitors of Plasmodium falciparum plasmepsin V (PMV) using virtual screening.
• To evaluate the efficacy and safety of identified compounds as potential anti-malarial drugs.

Main Methods:

• Ligand-based virtual screening of 5.5 million compounds against PMV.
• In vitro cellular assays to determine compound potency and IC50 values.
• In vivo efficacy testing using transgenic P. falciparum overexpressing PMV.

Main Results:

• Four novel plasmepsin inhibitors were identified.
• Two lead compounds demonstrated in vivo efficacy with IC50 values of 44.2 μm and 19.1 μm.
• Lead compounds showed no significant toxicity to human cells at tested concentrations.

Conclusions:

• Consensus virtual screening is an effective technique for designing novel ligands.
• Two lead compounds represent promising novel protease inhibitors for targeting malaria.