Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: Exploration of 7′-substitution of benzothiadiazine

Zhou, Yang; Webber, S. E.; Murphy, Douglas E.; Li, Liansheng; Dragovich, Peter S.; Tran, Chinh V.; Sun, Zhongxiang; Ruebsam, Frank; Shah, Anup; Tsan, Mei; Showalter, Richard E.; Patel, Rupal; Li, Bin; Zhao, Qiang; Han, Qinghong; Hermann, Thomas; Kissinger, Charles R.; LeBrun, Laurie A.; Sergeeva, Maria V.; Kirkovsky, Leo

doi:10.1016/j.bmcl.2008.01.007

Cited by 44 publications

(21 citation statements)

References 17 publications

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“…Palm I site inhibitors include multiple series of benzothiadiazine-containing compounds, which select resistant variants C316Y, M414T, Y448H, and G554D (19,20). The resistance profiles of the palm I site inhibitors and their overlap with the palm II site inhibitors are entirely consistent with published ligand-bound crystal structures of palm I and II site inhibitors (17,21).…”

supporting

confidence: 59%

See 1 more Smart Citation

In Vitro Activity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Kati

Koev

Irvin

et al. 2015

Antimicrob Agents Chemother

109

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supporting

confidence: 59%

“…The variants selected by dasabuvir were similar to those selected by the benzothiadiazine class of inhibitors, compounds that bind to the palm I site of NS5B (19)(20)(21). The palm I site overlaps with the palm II site near the C316 residue, as indicated by the fact that the C316Y variant is resistant to the known palm II inhibitor HCV-796.…”

Section: Discussionmentioning

confidence: 94%

In Vitro Activity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Kati

Koev

Irvin

et al. 2015

Antimicrob Agents Chemother

109

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“…A dataset containing 80 newly synthesized compounds (which also bind to the NNI III binding site of HCV NS5B polymerase) was collected from recent literatures [8,20,21], which were not included in the training and test set. The dataset was used as an external test set, which contains 38 active inhibitors and 42 weakly active inhibitors of NS5B polymerase.…”

Section: Resultsmentioning

confidence: 99%

Classification of HCV NS5B Polymerase Inhibitors Using Support Vector Machine

Wang

Yan

et al. 2012

IJMS

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Using a support vector machine (SVM), three classification models were built to predict whether a compound is an active or weakly active inhibitor based on a dataset of 386 hepatitis C virus (HCV) NS5B polymerase NNIs (non-nucleoside analogue inhibitors) fitting into the pocket of the NNI III binding site. For each molecule, global descriptors, 2D and 3D property autocorrelation descriptors were calculated from the program ADRIANA.Code. Three models were developed with the combination of different types of descriptors. Model 2 based on 16 global and 2D autocorrelation descriptors gave the highest prediction accuracy of 88.24% and MCC (Matthews correlation coefficient) of 0.789 on test set. Model 1 based on 13 global descriptors showed the highest prediction accuracy of 86.25% and MCC of 0.732 on external test set (including 80 compounds). Some molecular properties such as molecular shape descriptors (InertiaZ, InertiaX and Span), number of rotatable bonds (NRotBond), water solubility (LogS), and hydrogen bonding related descriptors performed important roles in the interactions between the ligand and NS5B polymerase.

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“…Discarding compounds with unspecified activity and undefined stereochemistry, data from fifteen published literatures with a wide spectrum of activities using standard HCV GT-1b NS5B polymerase bioassay were collected in this study [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. The in vitro biological activity IC 50 (μM) values were converted to pIC 50 (-log IC 50 ) values, which were used as dependent variables in QASAR analyses.…”

Section: Data Setsmentioning

confidence: 99%

“…They also investigated isoquinoline-benzoisothiazole analogs, supporting the concept that a mono-anionic species binds to the NS5B viral polymerase [37]. Anadys Pharmaceuticals Inc and Abbott Laboratories have published a series of papers addressing various aspects of the optimization of the structures such as quinolones, pyridazinones, pyridinones and aromatic ring of the benzothiadiazines, discussing the challenges in achieving both good potency and pharmacokinetic characteristics [38][39][40][41][42][43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Zhang

Li²,

Wang³

et al. 2011

CMC

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Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

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Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: Exploration of 7′-substitution of benzothiadiazine

Cited by 44 publications

References 17 publications

In Vitro Activity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

In Vitro Activity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Classification of HCV NS5B Polymerase Inhibitors Using Support Vector Machine

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

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