Virus NS5B Polymerase Inhibitors Research Articles

Computational insight to design new potential hepatitis C virus NS5B polymerase inhibitors with drug-likeness and pharmacokinetic ADMET parameters predictions

BackgroundHepatitis C virus (HCV) is considered a worldwide health problem since it affects over 3% of the population and causes 300,000 fatalities per year. Chronic infection causes high morbidity and mortality in patients, leading to liver cirrhosis, hepatocellular carcinoma, fibrosis, liver cancer, and other HCV-related illnesses. Finding novel and better HCV treatments is a top international health goal right now. As a result, the pressing need for new HCV antiviral drugs has fueled research into the structural requirements of NS5B polymerase inhibitors at a molecular basis.ResultsIn this study, an in silico technique was applied to study 79 compounds with HCV inhibitory bioactivity, with the best statistical results (R^{2}= 0.7051, Q^{2} = 0.6455, R_{{{text{pred}}}}^{2} = 0.6992, ^{{text{c}}} R_{{text{r}}}^{2} = 0.6570, SEE = 0.2694).ConclusionsThis QSAR investigation allowed the research team to evaluate the influence of straightforward descriptors, shedding insight into the critical elements that guide the design of innovative effective molecules. Most of the innovative effective molecules exhibited better binding affinity (− 195.6 kcal/mol) than dasabuvir the reference drug (− 171.0 kcal/mol) with the target receptor (hepatitis C virus NS5B RNA polymerase). ADMET prediction disclosed enhanced pharmacokinetic properties with lower MRTD (maximum tolerated dose) of some new derivatives.

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

Hepatitis C virus (HCV) infection is highly persistent and presents an unmet medical need requiring more effective treatment options. This has spurred intensive efforts to discover novel anti-HCV agents. The RNA-dependent RNA polymerase (RdRp), NS5B of HCV, constitutes a selective target for drug discovery due to its absence in human cells; also, it is the centerpiece for viral replication. Here, we synthesized novel pyrrole, pyrrolo[2,3-d]pyrimidine and pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives. The non-toxic doses of these compounds on Huh 7.5 cell line were determined and their antiviral activity against HCVcc genotype 4a was examined. Compounds 7j, 7f, 5c, 12i and 12f showed significant anti HCV activity. The percent of reduction for the non-toxic doses of 7j, 7f, 5c, 12i and 12f were 90%, 76.7±5.8%, 73.3±5.8%, 70% and 63.3±5.8%, respectively. The activity of these compounds was interpreted by molecular docking against HCV NS5B polymerase enzyme.

3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion and hepatitis C virus (HCV) infection is a global health threat. The HCV NS5B polymerase, an RNA dependent RNA polymerase (RdRp) and an essential role in the replication of the virus, has no functional equivalent in mammalian cells. So the research and development of efficient NS5B polymerase inhibitors provides a great strategy for antiviral therapy against HCV. A combined three-dimensional quantitative structure–activity relationship (QSAR) modeling was accomplished to profoundly understand the structure-activity correlation of a train of indole-based inhibitors of the HCV NS5B polymerase to against HCV. A comparative molecular similarity indices analysis (COMSIA) model as the foundation of the maximum common substructure alignment was developed. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.627 and non-cross-validated r2 value was 0.943. In addition, the results of internal validations of bootstrapping and Y-randomization confirmed the rationality and good predictive ability of the model, as well as external validation (the external predictive correlation coefficient rext2 = 0.629). The information obtained from the COMSIA contour maps enables the interpretation of their structure–activity relationship. Furthermore, the molecular docking study of the compounds for 3TYV as the protein target revealed important interactions between active compounds and amino acids, and several new potential inhibitors with higher activity predicted were designed basis on our analyses and supported by the simulation of molecular docking. Meanwhile, the OSIRIS Property Explorer was introduced to help select more satisfactory compounds. The satisfactory results from this study may lay a reliable theoretical base for drug development of hepatitis C virus NS5B polymerase inhibitors.

Novel indole derivatives as hepatitis C virus NS5B polymerase inhibitors: Pharmacophore modeling and 3D QSAR studies

Hepatitis C Virus (HCV) encodes its own RNA dependent RNA polymerase (NS5b) in order to replicate its genome. An efficient pharmacophore was identified, by executing structural analysis of a set of 49 indole-based inhibitors of the HCV NS5B polymerase. Identified pharmacophoric features, two hydrophobic regions, and 4 aromatic rings i.e. HHRRRR.649. Ligand based 3D-QSAR was performed, partial least square regression analysis was employed which gave a regression coefficient R2 of 0.98 and Q2 of 0.88, and Pearson-R of 0.96.

Activity prediction of hepatitis C virus NS5B polymerase inhibitors of pyridazinone derivatives

A valid quantitative structure–activity relationship (QSAR) model was applied to predict IC50 value of pyridazinone derivatives as HCV NS5B protease inhibitors. Various chemical descriptors were calculated by E-Dragon. Six character variables were selected though stepwise multiple linear regression (stepwise-MLR), which included MATS6m, RDF055e, Mor31u, G3m, R1m and R4v+. In addition, twenty-three molecular descriptors were obtained via uninformative variable elimination by partial least squares (UVE-PLS). The selected descriptors using two approaches were basically the same type of molecular descriptors. Subsequently, partial least squares (PLS) and particle swarm optimization support vector machine (PSO-SVM) were utilized to establish the linear and nonlinear models by two set of descriptors and their activity data, respectively. The predictive performance of the proposed models was evaluated by the strict criteria. The results showed that the predictive power of the PSO-SVM models was better than the corresponding PLS models. Thus, it can be inferred that the PSO-SVM models were robust and satisfactory, and could provide some feasible and effective information to design and synthesis of highly potent HCV NS5B polymerase inhibitors.

Evaluation of the effect of mericitabine at projected therapeutic and supratherapeutic doses on cardiac repolarization in healthy subjects: A thorough QT/QTc study.

Mericitabine, the di-isobutyl ester prodrug of the cytidine nucleoside analog, is a potent and selective hepatitis C virus NS5B polymerase inhibitor. This thorough QT/QTc study evaluated the effect of mericitabine on cardiac repolarization in healthy subjects. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study. A total of 60 subjects were enrolled and randomized to receive a single dose of mericitabine 1,500 mg, 9,000 mg, moxifloxacin 400 mg and placebo in randomly assigned treatment sequences, with at least 14 days between doses. The primary endpoint was the mean difference in baseline-adjusted QT interval using a study-specific correction method (QTcS) between mericitabine and placebo. The upper one-sided 95% confidence interval for the placebo-subtracted change from baseline in QTcS was <10 milliseconds and the mean difference from placebo was <5 milliseconds at all time points for both mericitabine doses. The positive control moxifloxacin caused a pronounced increase in QTcS that peaked 4 hours after oral administration. Furthermore, there was no trend of a concentration-dependent effect of mericitabine on QTcS. In conclusion, mericitabine does not have a clinically or statistically significant effect on cardiac repolarization in healthy subjects at single doses up to 9,000 mg.

Sofosbuvir: First Global Approval

Sofosbuvir (Solvadi™), a nucleotide analogue hepatitis C virus NS5B polymerase inhibitor, is under development with Gilead Sciences for the once-daily, oral treatment of chronic hepatitis C. Oral sofosbuvir has been approved in the US for the treatment of chronic hepatitis C as a component of a combination antiviral regimen. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of sofosbuvir for the treatment of chronic hepatitis C. This article summarizes the milestones in the development of sofosbuvir leading to this first approval for chronic hepatitis C.

Virtual screening of imidazole analogs as potential hepatitis C virus NS5B polymerase inhibitors

AbstractHepatitis C virus (HCV) infection is a global health threat and current therapies warrant the need for novel HCV therapies. Several synthetic analogs targeting HCV serine protease and RNA-dependent RNA polymerase have entered clinical development. To investigate the novel HCV NS5B RdRp polymerase inhibitor, screening of a designed data set consisting of benzimidazole analogs by the FlexX docking approach was performed. Binding interactions at the active sites (PDB ID: 2DXS) were evaluated leading to the rationalization of further synthesis and evaluation procedures.

QSAR based modeling of hepatitis C virus NS5B inhibitors

QSAR analysis on a series of 13 derivatives of 5-hydroxy-3-(2H)-pyridazinone as hepatitis C virus NS5B polymerase inhibitors was performed. The inhibitory activities of these compounds were found to increase with density (D), index of refractivity (Ior), surface tension (St), electronegativity (Xeq) and decrease with the balaben centric index (Bac), balaben distance connectivity index (J) and zero order connectivity (X0) along with the indicator parameter. Excellent results were obtained from regression upon introduction of the indicator parameter. The results are critically discussed on the basis of regression data and cross validation technique.

Synthesis and biological activity of heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone derivatives as hepatitis C virus NS5B polymerase inhibitors

Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.

4-Thiazolidinones: a novel class of hepatitis C virus NS5B polymerase inhibitors

In a quest to identify novel compounds targeting HCV viral replicase, we evaluated a new series of 4-thiazolidinone derivatives (18 compounds). Our in vitro NS5B RdRp inhibition analysis with a series of 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid [2-(5-nitro-2-furyl / substituted phenyl)-4-thiazolidinone-3-yl] amides (1-7) yielded IC50 values ranging between 45-75 microM. Of these, lead compound 6: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid[2-(2-fluorophenyl)-4-thiazolidinone-3-yl]amide exhibited an IC50 value of 48 microM and inhibited NS5B non-competitively with respect to UTP and exhibited a mixed mode of inhibition with respect to RNA. Molecular docking of thiazolidinone derivatives within the allosteric site of NS5B yielded significant correlation between their calculated binding affinity and IC50 values. Taken together, these data suggest that the 4-thiazolidinone scaffold may be optimized for generating new analogues with improved anti-NS5B potency.

3D QSAR and Molecular Docking Studies of Benzimidazole Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors

The urgent need for novel HCV antiviral agents has provided an impetus for understanding the structural requisites of NS5B polymerase inhibitors at the molecular level. Toward this objective, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 67 HCV NS5B polymerase inhibitors were performed using two methods. First, ligand-based 3D QSAR studies were performed based on the lowest energy conformations employing the atom fit alignment method. Second, receptor-based 3D QSAR models were derived from the predicted binding conformations obtained by docking all NS5B inhibitors at the allosteric binding site of NS5B (PDB ID: 2dxs). Results generated from the ligand-based model were found superior (r2cv values of 0.630 for CoMFA and 0.668 for CoMSIA) to those obtained by the receptor-based model (r2cv values of 0.536 and 0.561 for CoMFA and CoMSIA, respectively). The predictive ability of the models was validated using a structurally diversified test set of 22 compounds that had not been included in a preliminary training set of 45 compounds. The predictive r2 values for the ligand-based CoMFA and CoMSIA models were 0.734 and 0.800, respectively, while the corresponding predictive r2 values for the receptor-based CoMFA and CoMSIA models were 0.538 and 0.639, respectively. The greater potency of the tryptophan derivatives over that of the tyrosine derivatives was interpreted based on CoMFA steric and electrostatic contour maps. The CoMSIA results revealed that for a NS5B inhibitor to have appreciable inhibitory activity it requires hydrogen bond donor and acceptor groups at the 5-position of the indole ring and an R substituent at the chiral carbon, respectively. Interpretation of the CoMFA and CoMSIA contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. Taken together, the present 3D QSAR models were found to accurately predict the HCV NS5B polymerase inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the benzimidazole derivatives in the data set.

Discovery of Proline Sulfonamides as Potent and Selective Hepatitis C Virus NS5b Polymerase Inhibitors. Evidence for a New NS5b Polymerase Binding Site

Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.