Isothiazoles as active-site inhibitors of HCV NS5B polymerase

2007 ◽  
Vol 17 (1) ◽  
pp. 28-33 ◽  
Author(s):  
Shunqi Yan ◽  
Todd Appleby ◽  
Esmir Gunic ◽  
Jae Hoon Shim ◽  
Tania Tasu ◽  
...  
Keyword(s):  
Active Site ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Novel Guanosine Derivatives as Anti-HCV NS5b Polymerase: A QSAR and Molecular Docking Study

2019 ◽  
Vol 15 (2) ◽  
pp. 130-137 ◽  
Author(s):  
Abdo A. Elfiky
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Active Site ◽  
Docking Study ◽  
Binding Affinities ◽  
Molecular Docking Study ◽  
Docking Calculations ◽  
Quantitative Structure Activity Relationships ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Background: IDX-184 is a guanosine derivative having a potent inhibitory performance against HCV NS5b polymerase. Objective: To test three different groups of 2'C - modified analogues of guanosine nucleotide against HCV polymerase. Method: Using combined Quantitative Structure-Activity Relationships (QSAR) and molecular docking, the suggested compounds are studied. Results: Examining the docked structures of the compounds with experimentally solved NS5b structure (PDB ID: 2XI3) revealed that most of the compounds have the same mode of interaction as that of guanosine nucleotide and hence, NS5b inhibition is possible. Conclusion: It is revealed that sixteen modifications have a better binding affinity to NS5b compared to guanosine. In addition, seven more compounds are better in NS5b binding compared to the approved drug, sofosbuvir, and the compound under clinical trials, IDX-184. Hence, these compounds could be potent HCV NS5b inhibitors. Summary Points: Novel guanosine modifications were introduced in silico and optimized using QM. QSAR and docking calculations are performed to test the binding affinity of the compounds to HCV NS5b active site. Comparison between the binding affinities and the mode of interactions of the compounds and both GTP and IDX-184 is performed. Structural mining to quantify the mode of binding of the compounds to NS5b active site pocket.

Active Site Inhibitors of HCV NS5B Polymerase. The Development and Pharmacophore of 2-Thienyl-5,6-dihydroxypyrimidine-4-carboxylic Acid.

ChemInform ◽  
2005 ◽  
Vol 36 (4) ◽  
Author(s):  
Ian Stansfield ◽  
Salvatore Avolio ◽  
Stefania Colarusso ◽  
Nadia Gennari ◽  
Frank Narjes ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Active Site ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid

2004 ◽  
Vol 14 (20) ◽  
pp. 5085-5088 ◽  
Author(s):  
Ian Stansfield ◽  
Salvatore Avolio ◽  
Stefania Colarusso ◽  
Nadia Gennari ◽  
Frank Narjes ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Active Site ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

No influence of antiretroviral therapy on the mutation rate of the HCV NS5B polymerase in HIV/HCV-coinfected patients

2012 ◽  
Vol 95 (2) ◽  
pp. 67-71 ◽  
Author(s):  
Federico Alejandro Di Lello ◽  
Juan Macias ◽  
Zulema Plaza ◽  
Silvia García-Rey ◽  
Vicente Soriano ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Mutation Rate ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

scholarly journals Discovery of N-Arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide Derivatives as HCV NS5B Polymerase Inhibitors

ChemMedChem ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. 850-860 ◽  
Author(s):  
Ravindra Ramesh Deore ◽  
Grace Shiahuy Chen ◽  
Pei-Teh Chang ◽  
Ting-Rong Chern ◽  
Shin-Yu Lai ◽  
...  
Keyword(s):  
Polymerase Inhibitors ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase — Acylsulfonamides and acylsulfamides as carboxylic acid replacements

2013 ◽  
Vol 91 (1) ◽  
pp. 66-81 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
René Coulombe ◽  
James Gillard ◽  
Christian Brochu ◽  
Jianmin Duan ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Carboxylic Acid ◽  
Allosteric Inhibitors ◽  
Subgenomic Replicon ◽  
Structure Activity ◽  
Hcv Ns5b ◽  
Acid Function ◽  
Ns5b Polymerase

Acylsulfonamide and acylsulfamide as surrogates for the carboxylic acid function of N-acetamide-indole-6-carboxylic acids were evaluated as allosteric inhibitors of hepatitis C virus (HCV) NS5B polymerase. Several analogs displayed excellent antiviral potency against both 1a and 1b HCV genotypes in cell-based subgenomic replicon assays. Structure–activity relationships (SAR) are discussed in the context of the crystal structure of an inhibitor − NS5B polymerase complex. Absorption, distribution, metabolism, and excretion pharmacokinetic (ADME-PK) properties of this class of inhibitors are also described.

I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles

2011 ◽  
Vol 21 (18) ◽  
pp. 5336-5341 ◽  
Author(s):  
Gopinadhan N. Anilkumar ◽  
Charles A. Lesburg ◽  
Oleg Selyutin ◽  
Stuart B. Rosenblum ◽  
Qingbei Zeng ◽  
...  
Keyword(s):  
Carboxylic Acids ◽  
Polymerase Inhibitors ◽  
Hcv Ns5b ◽  
Ns5b Polymerase
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