title: Modeling of Plasmodium falciparum Telomerase Reverse Transcriptase Ternary Complex: Repurposing of Nucleoside Analog Inhibitors.
abstract: The Plasmodium falciparum telomerase reverse transcriptase (PfTERT) is a ribonucleoprotein that assists the maintenance of the telomeric ends of chromosomes by reverse transcription of its own RNA subunit. It represents an attractive therapeutic target for eradication of the plasmodial parasite at the asexual liver stage. Automated modeling using MUSTER and knowledge-based techniques were used to obtain a three-dimensional model of the active site of reverse transcriptase domain of PfTERT, which is responsible for catalyzing the addition of incoming dNTPs to the growing DNA strand in presence of divalent magnesium ions. Further, the ternary complex of the active site of PfTERT bound to a DNA-RNA duplex was also modeled using Haddock server and represents the functional form of the enzyme. Initially, established nucleoside analog inhibitors of PfTERT, AZTTP, and ddGTP were docked in the modeled binding site of the PfTERT ternary complex using AutoDock v4.2. Subsequently, docking studies were carried out with 14 approved nucleoside analog inhibitors. Docking studies predicted that floxuridine, gemcitabine, stavudine, and vidarabine have high affinity for the PfTERT ternary complex. Further analysis on the basis of known side effects led us to propose repositioning of vidarabine as a suitable drug candidate for inhibition of PfTERT.
authors.affiliation: Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology , Dwarka, New Delhi, India .
authors.forename: Pallavi
authors.initials: P
authors.lastname: Mohanty
authors.affiliation: Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology , Dwarka, New Delhi, India .
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology , Dwarka, New Delhi, India .
authors.forename: Sonika
authors.initials: S
authors.lastname: Bhatnagar
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D003848:Deoxyguanine Nucleotides / Q000037:antagonists & inhibitors / Q000235:genetics; D054306:Dideoxynucleotides / Q000037:antagonists & inhibitors / Q000235:genetics; D058492:Drug Repositioning / Q000379:methods*; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D017434:Protein Structure, Tertiary; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D013942:Thymine Nucleotides / Q000037:antagonists & inhibitors / Q000235:genetics; D014740:Vidarabine / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors
chemical_list: D000962:Antimalarials; D000963:Antimetabolites; D003848:Deoxyguanine Nucleotides; D054306:Dideoxynucleotides; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D015215:Zidovudine; C031709:2',3'-dideoxyguanosine 5'-triphosphate; C052873:zidovudine triphosphate; D012194:RNA-Directed DNA Polymerase; D019098:Telomerase; D014740:Vidarabine; D008274:Magnesium