Targeting the Plasmodium falciparum Plasmepsin V by ligand-based virtual screening
| العنوان: | Targeting the Plasmodium falciparum Plasmepsin V by ligand-based virtual screening |
|---|---|
| المؤلفون: | Gustavo Henrique Goulart Trossini, Thales Kronenberger, Carsten Wrenger, Vinícius Gonçalves Maltarollo, Kamila Anna Meissner |
| المصدر: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Cell Survival, medicine.medical_treatment, Plasmodium falciparum, Plasmepsin, Protozoan Proteins, Pharmacology, Ligands, 01 natural sciences, Biochemistry, Antimalarials, Inhibitory Concentration 50, In vivo, Catalytic Domain, Drug Discovery, Sense (molecular biology), medicine, Potency, Aspartic Acid Endopeptidases, Humans, Protease Inhibitors, Viability assay, Virtual screening, Protease, Binding Sites, biology, Organisms, Genetically Modified, ATIVAÇÃO ENZIMÁTICA, 010405 organic chemistry, Chemistry, Organic Chemistry, Hep G2 Cells, biology.organism_classification, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Molecular Medicine |
| الوصف: | 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. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::063e851cc4f195628cae44a1b0c8bdff |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....063e851cc4f195628cae44a1b0c8bdff |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |