Discovery of substituted N-phenylbenzenesulphonamides as a novel class of non-nucleoside hepatitis C virus polymerase inhibitors

May, Marina M.; Brohm, Dirk; Harrenga, Axel; Marquardt, Tobias; Riedl, Bernd; Kreuter, J.; Zimmermann, Holger; Ruebsamen‐Schaeff, Helga; Urban, Andreas

doi:10.1016/j.antiviral.2012.04.008

Cited by 9 publications

(9 citation statements)

References 47 publications

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“…In this study, 1029 compounds were used to build the QSAR model, which comprised 579 HCV NS5B inhibitors, (PIC 50 < ~14) and 450 non-HCVNS5B inhibitors (PIC 50 > ~14) 45 . These compounds were collected from previous studies and extracted from the BindingDB and CHEMBL databases 10 , 46 . The chemical descriptors were calculated using the DataWarrior package 47 .…”

Section: Methodsmentioning

confidence: 99%

Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System

Elaziz

Moemen

Hassanien

et al. 2018

Sci Rep

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The global prevalence of hepatitis C Virus (HCV) is approximately 3% and one-fifth of all HCV carriers live in the Middle East, where Egypt has the highest global incidence of HCV infection. Quantitative structure-activity relationship (QSAR) models were used in many applications for predicting the potential effects of chemicals on human health and environment. The adaptive neuro-fuzzy inference system (ANFIS) is one of the most popular regression methods for building a nonlinear QSAR model. However, the quality of ANFIS is influenced by the size of the descriptors, so descriptor selection methods have been proposed, although these methods are affected by slow convergence and high time complexity. To avoid these limitations, the antlion optimizer was used to select relevant descriptors, before constructing a nonlinear QSAR model based on the PIC50 and these descriptors using ANFIS. In our experiments, 1029 compounds were used, which comprised 579 HCVNS5B inhibitors (PIC50 < ~14) and 450 non-HCVNS5B inhibitors (PIC50 > ~14). The experimental results showed that the proposed QSAR model obtained acceptable accuracy according to different measures, where was 0.952 and 0.923 for the training and testing sets, respectively, using cross-validation, while was 0.8822 using leave-one-out (LOO).

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Section: Methodsmentioning

confidence: 99%

Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System

Elaziz

Moemen

Hassanien

et al. 2018

Sci Rep

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“…A total of 1029 compounds (see S1 – S3 Tables in supporting information), including 579 positives (NS5B inhibitors, IC 50 ≤ 400 nM) and 450 negatives (NS5B noninhibitors, IC 50 ≥ 600 nM) [ 35 ], were selected from the literature, Binding DB and CHEMBL database [ 36 – 49 ]. The 1029 compounds were first divided into different clusters on the basis of their scaffolds.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Hepatitis C Virus NS5B Polymerase Inhibitors by Combining Random Forest, Multiple e-Pharmacophore Modeling and Docking

Wei

Qing

et al. 2016

PLoS ONE

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The NS5B polymerase is one of the most attractive targets for developing new drugs to block Hepatitis C virus (HCV) infection. We describe the discovery of novel potent HCV NS5B polymerase inhibitors by employing a virtual screening (VS) approach, which is based on random forest (RB-VS), e-pharmacophore (PB-VS), and docking (DB-VS) methods. In the RB-VS stage, after feature selection, a model with 16 descriptors was used. In the PB-VS stage, six energy-based pharmacophore (e-pharmacophore) models from different crystal structures of the NS5B polymerase with ligands binding at the palm I, thumb I and thumb II regions were used. In the DB-VS stage, the Glide SP and XP docking protocols with default parameters were employed. In the virtual screening approach, the RB-VS, PB-VS and DB-VS methods were applied in increasing order of complexity to screen the InterBioScreen database. From the final hits, we selected 5 compounds for further anti-HCV activity and cellular cytotoxicity assay. All 5 compounds were found to inhibit NS5B polymerase with IC50 values of 2.01–23.84 μM and displayed anti-HCV activities with EC50 values ranging from 1.61 to 21.88 μM, and all compounds displayed no cellular cytotoxicity (CC50 > 100 μM) except compound N2, which displayed weak cytotoxicity with a CC50 value of 51.3 μM. The hit compound N2 had the best antiviral activity against HCV, with a selective index of 32.1. The 5 hit compounds with new scaffolds could potentially serve as NS5B polymerase inhibitors through further optimization and development.

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“…It entered clinical development, but failed to demonstrate significant efficacy and development was therefore discontinued (Howe et al 2004;Howe et al 2006). Recently, substituted N-phenylbenzenesulphonamides were also shown to inhibit HCV genotype 1a and 1b replication in vitro (May et al 2012).…”

Section: Thumb II Inhibitorsmentioning

confidence: 99%

Hepatitis C Virus-Specific Directly Acting Antiviral Drugs

Neyts

Vliegen

Abrignani

et al. 2013

Current Topics in Microbiology and Immunology

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The major targets for direct-acting antivirals (DAAs) are the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers several target sites: the catalytic domain for nucleoside/nucleotide analogs and different allosteric sites for non-nucleoside inhibitors. Two protease inhibitors have already been approved and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development pipeline. Not only these agents can achieve very high cure rates when combined with PEG-IFN and RBV, but have also started to provide promising results when combined in IFN-free, all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small molecule drug development are emerging, such as p7 or NS4B. Current research is focusing on defining the most efficacious DAA combination regimens, i.e., those which provide the highest rates of viral eradication, broadest spectrum of action, minimal or no clinical resistance, shortest treatment duration, and good tolerability.

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Discovery of substituted N-phenylbenzenesulphonamides as a novel class of non-nucleoside hepatitis C virus polymerase inhibitors

Cited by 9 publications

References 47 publications

Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System

Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System

Discovery of Novel Hepatitis C Virus NS5B Polymerase Inhibitors by Combining Random Forest, Multiple e-Pharmacophore Modeling and Docking

Hepatitis C Virus-Specific Directly Acting Antiviral Drugs

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