title: Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach.
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.
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Nagasundaram
authors.initials: N
authors.lastname: N
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu 632014, India.
authors.forename: George Priya Doss
authors.initials: GP
authors.lastname: C
authors.affiliation: Department of Bioinformatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Karthick
authors.initials: K
authors.lastname: V
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu 632014, India.
authors.forename: Thirumal Kumar
authors.initials: TK
authors.lastname: D
authors.affiliation: Department of Clinical Microbiology, Christian Medical College, Vellore 632014, Tamil Nadu, India.
authors.forename: Balaji
authors.initials: B
authors.lastname: V
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu 632014, India.
authors.forename: Siva
authors.initials: S
authors.lastname: R
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Ge
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D062105:Molecular Docking Simulation / Q000379:methods; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics
chemical_list: C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D050505:Mutant Proteins; D000252:Calcium-Transporting ATPases