Design, synthesis, assessment, and molecular docking of novel pyrrolopyrimidine (7-deazapurine) derivatives as non-nucleoside hepatitis C virus NS5B polymerase inhibitors

Mohamed, Mosaad S.; Sayed, Amira I.; Khedr, Mohammed A.; Soror, Sameh H.

doi:10.1016/j.bmc.2016.03.046

Cited by 25 publications

(16 citation statements)

References 43 publications

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“…These are divided in two groups: structural proteins (highly basic core protein C and the glycoproteins E1 and E2) and nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) . NS5B has been shown to be a promising target for therapeutics due to its crucial role in replicating the viral genome . The fact that mammalian cells lack a homologous enzyme also makes NS5B an attractive drug target due to the potential for selective inhibition of viral replication.…”

Section: Introductionmentioning

confidence: 99%

Molecular simulations to delineate functional conformational transitions in the HCV polymerase

2016

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Hepatitis C virus (HCV) is a global health concern for which there is no vaccine available. The HCV polymerase is responsible for the critical function of replicating the RNA genome of the virus. Transitions between at least two conformations (open and closed) are necessary to allow the enzyme to replicate RNA. In this study, molecular dynamic simulations were initiated from multiple crystal structures to understand the free energy landscape (FEL) explored by the enzyme as it interconverts between these conformations. Our studies reveal the location of distinct states within the FEL as well as the molecular interactions associated with these states. Specific hydrogen bonds appear to play a key role in modulating conformational transitions. This knowledge is essential to elucidate the role of these conformations in replication and may also be valuable in understanding the basis by which this enzyme is inhibited by small molecules. © 2016 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

Molecular simulations to delineate functional conformational transitions in the HCV polymerase

2016

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“…The docking protocol was “rigid receptor,” and the solvent molecules were conserved for the docking. Triangle matcher was used as placement method, London dG was used as the first rescoring method, and affinity dG was used as the second …”

Section: Methodsmentioning

confidence: 99%

“…Triangle matcher was used as placement method, London dG was used as the first rescoring method, and affinity dG was used as the second. 43…”

Section: Molecular Modeling Studymentioning

confidence: 99%

Radioiodination and biological distribution of a new s‐triazine derivative for tumor uptake evaluation

Motaleb

Ibrahim

Sarhan

et al. 2018

Labelled Comp Radiopharmac

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A newly synthesized s-triazine derivative 1,1',1″-(((1,3,5-triazine-2,4,6-triyl) tris (azanediyl)) tris (benzene-4,1-diyl))tris (ethan-1-one), (1), was synthesized as a part of an ongoing research for development of novel s-triazine-based radiopharmaceuticals. In-vitro cell viability assay against different human cancer cell lines showed very promising inhibitory activity of the synthesized compound. This finding encouraged the radioiodination of 1 to study the degree of its localization in tumor site for evaluating the possibility of its use as a tumor imaging agent. The biodistribution study showed good localization of the radioiodinated derivative 2 at tumor site following i.v. administration in solid tumor-bearing mice. Finally, in a trial to understand the mechanism of the anticancer effect exerted by 1, a target prediction study and a docking study were performed. The results of the first study showed that focal adhesion kinase is a possible target for compound 1 and the docking study confirmed successful binding of both compound 1 and its radioiodinated derivative 2 to the binding site of focal adhesion kinase. As a conclusion, the results of this study suggest that, compound 2 could be used as a potential agent for tumor imaging after preclinical trials.

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“…By contrast, STV is recently in phase 2 clinical trials and shows potent antiviral activity for HCV1 infected patients. Ongoing research efforts have been gained in order to develop new DAAs, such as novel pyrrolopyrimidine derivatives, found to show a significant anti HCV activity …”

Section: Introductionmentioning

confidence: 99%

Structural Modeling of New Polymorphism Clusters of HCV Polymerase Isolated from Direct‐Acting Antiviral Naïve Patients: Focus on Dasabuvir and Setrobuvir Binding Affinity

et al. 2018

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Management of Hepatitis C virus infection changed after the development of direct-acting antiviral agents, including NS5B polymerase inhibitors. However, the presence of non-synonymous substitutions could lead to therapy failure. Herein, we analyzed novel polymorphism clusters in NS5B polymerase from Hepatitis C virus (HCV) subtype 1b isolates of direct-acting antivirals (DAAs) naïve patients by Sanger population sequencing. By means of computational approaches, we investigated the impact of these polymorphisms on the apo-polymerase stability and on the binding affinity of dasabuvir and setrobuvir.Our thermodynamic and structural analysis highlighted that some mutational patterns could enhance or reduce the drug's affinity if compared to the wild-type complexes and allowed us to well characterize the binding mode of the known drugs into the NS5B binding pocket. Our computational findings agreed with dasabuvir and setrobuvir in vitro reduced binding affinities against C316N mutant and could be useful in guiding the therapeutic approaches in presence of specific natural polymorphisms on HCV polymerase.

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Design, synthesis, assessment, and molecular docking of novel pyrrolopyrimidine (7-deazapurine) derivatives as non-nucleoside hepatitis C virus NS5B polymerase inhibitors

Cited by 25 publications

References 43 publications

Molecular simulations to delineate functional conformational transitions in the HCV polymerase

Molecular simulations to delineate functional conformational transitions in the HCV polymerase

Radioiodination and biological distribution of a new s‐triazine derivative for tumor uptake evaluation

Structural Modeling of New Polymorphism Clusters of HCV Polymerase Isolated from Direct‐Acting Antiviral Naïve Patients: Focus on Dasabuvir and Setrobuvir Binding Affinity

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