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Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach
- Source :
- Scientific Reports
- Publication Year :
- 2016
-
Abstract
- Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs.
- Subjects :
- 0301 basic medicine
In silico
030106 microbiology
Mutant
Plasmodium falciparum
Drug Resistance
Drug resistance
Computational biology
Calcium-Transporting ATPases
Pharmacology
medicine.disease_cause
Article
03 medical and health sciences
Antimalarials
parasitic diseases
medicine
Humans
Artemisinin
Malaria, Falciparum
Virtual screening
Mutation
Multidisciplinary
biology
biology.organism_classification
medicine.disease
Artemisinins
Molecular Docking Simulation
030104 developmental biology
Mutant Proteins
Malaria
medicine.drug
Protein Binding
Subjects
Details
- ISSN :
- 20452322 and 10595058
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.doi.dedup.....4d79f20f962096b86610207ec06618e9