Modeling of Plasmodium falciparum Telomerase Reverse Transcriptase Ternary Complex: Repurposing of Nucleoside Analog Inhibitors.
Assay Drug Dev Technol
; 13(10): 628-37, 2015 Dec.
Article
en En
| MEDLINE
| ID: mdl-26690766
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
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ADN Polimerasa Dirigida por ARN
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Telomerasa
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Inhibidores de la Transcriptasa Inversa
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Reposicionamiento de Medicamentos
/
Antimaláricos
/
Nucleósidos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Assay Drug Dev Technol
Asunto de la revista:
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
India