Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Language

English

Abstract

Artemisinin resistance in Plasmodium falciparumthreatens 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 silicoelucidation 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 vivoexperiments as possible candidates for the designing of new potential antimalarial drugs.

Publication Date

7-2016

Source Publication Title

Scientific Reports

Volume

6

Start Page

Article number: 30106 (2016)

Publisher

Nature Publishing Group

Peer Reviewed

1

Copyright

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funder

This work was supported by the Research Grants Council of Hong Kong 212613 and Faculty Research Grant of Hong Kong Baptist University FRG/14-15/063 and FRG2/13-14/056. The authors take this opportunity to thank the management of VIT University, Galgotias University and CMCH Vellore for providing the facilities and encouragement to carry out this work.

DOI

10.1038/srep30106

Link to Publisher's Edition

http://dx.doi.org/10.1038/srep30106

ISSN (print)

20452322

ISSN (electronic)

20452322

Additional Files

JA-5190-28388_suppl.pdf (1799 kB)

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