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.
Highlights
The medicinal use of artemisinin from sweet wormwood (Artemisia annua) was explored in 1970 by Chinese scientist; since it serves as a primary chemotherapy agent in antimalarial treatment
We carried out molecular modeling of malaria PfATP6 protein and molecular docking between wild type PfATP6-Artemisinin and mutant type (L263D, L263E and L263K)-Artemisinin to elucidate the detailed mechanism of binding action
In BLAST sequence similarity analysis PfATP6 of Plasmodium falciparum obtained highest sequence homology (45% identity) with Endoplasmic Reticulum Ca2+-Atpase (SERCA) from the bovine muscle of Bos taurus
Summary
The medicinal use of artemisinin (qinghaosu) from sweet wormwood (Artemisia annua) was explored in 1970 by Chinese scientist; since it serves as a primary chemotherapy agent in antimalarial treatment. Thapsigargin is considered as a highly selective inhibitor of Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) Based on this it was hypothesized that artemisinin may act in a similar way, but selectively to inhibit the SERCA of the malarial parasite. Recent report from Uhlemann et al in 201220 stated the reconfirmation of their previous conclusion that single amino acid mutations in PfATP6 can abolish sensitivity to artemisinin, as shown by the results obtained with PfATP6 mutants L263D, L263E and L263K. These observations hypothesised that mutations in the particular residue L263 residing in drug binding pocket might affect the affinity of the drug and consecutively cause decreased susceptibility to artemisinin. To ensure the stability of protein-ligand complexes 50 ns united atom molecular dynamics simulation was performed thrice for the wild type and mutant type PfATP6-Artemisinin and mutant PfATP6-Virtually screened compounds
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