School of Chinese Medicine
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.
Source Publication Title
Article number: 30106 (2016)
Nature Publishing Group
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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.
Link to Publisher's Edition
Nagasundaram, N., Doss, G., Chakraborty, C., Karthick, V., Kumar, D., Balaji, V., Siva, R., Lu, A., Zhang, G., & Zhu, H. (2016). Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach. Scientific Reports, 6, Article number: 30106 (2016). https://doi.org/10.1038/srep30106