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 5: Exploration of pyridazinones containing 6-amino-substituents

Dragovich, Peter S.; Blazel, Julie K.; Ellis, David; Han, Qinghong; Kamran, Ruhi; Kissinger, Charles R.; LeBrun, Laurie A.; Li, Liansheng; Murphy, Douglas E.; Noble, Michael A.; Patel, Rupal; Ruebsam, Frank; Sergeeva, Maria V.; Shah, Anup; Showalter, Richard E.; Tran, Chinh V.; Tsan, Mei; Webber, S. E.; Kirkovsky, Leo; Zhou, Yang

doi:10.1016/j.bmcl.2008.08.094

Cited by 24 publications

(15 citation statements)

References 24 publications

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“…62 Visual inspection of the downloaded crystal structures revealed that the structures could be classified into seven groups based on their different binding sites in the enzyme as well as on enzyme conformation. 14 PDB IDs were selected for cross-docking in the seven groups as follows: 1 ] 1NHU 63 (Thumb) 2 ] 2BRK, 2WHO 64 (Thumb) 3 ] 2D3Z 65 , 2D41 65 , 2GIR [Thumb] 4 ] 3HKY 66 (Palm) 5 ] 2HAI 67 (Thumb, Finger), 2WRM (Thumb 2), 3FRZ 68 (Thumb) 6 ] 2GIQ (Thumb 2), 3H2L 69 (Palm), 3H5S 70 (Palm) 7 ] 3E51 71 , 3H5U 69 (Palm).…”

Section: Resultsmentioning

confidence: 99%

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods

Weidlich

Filippov

Brown

et al. 2013

Bioorganic & Medicinal Chemistry

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Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ≤ 0.95 μM. We applied our SAR models to various drug-like databases and identified novel chemical scaffolds for NS5B inhibitors. Subsequent in vitro antiviral assays suggested a new activity for an existing prodrug, Candesartan cilexetil, which is currently used to treat hypertension and heart failure but has not been previously tested for anti-HCV activity. We also identified NS5B inhibitors with two novel non-nucleoside chemical motifs.

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Section: Resultsmentioning

confidence: 99%

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods

Weidlich

Filippov

Brown

et al. 2013

Bioorganic & Medicinal Chemistry

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“…5‐amino substituted derivatives were also far less active, except for a couple of compounds. Among them, 13c showed an interesting inhibitory value (IC 50 = 14 nM) …”

Section: Palm Pocket I Inhibitorsmentioning

confidence: 99%

“…Among them, 13c showed an interesting inhibitory value (IC 50 = 14 nM). 23 Based on previous results on the pyridazinone core, the pyrrolo[1,2-b]pyridazinone moiety was assessed by Anadys Pharmaceuticals. Interesting compounds emerged from this study, such as 15 which showed good inhibition (IC 50 < 10 nM).…”

Section: Effects Of Quinolinone Heterocyclic Core Modifications: Pyrimentioning

confidence: 99%

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

et al. 2012

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Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.

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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 5: Exploration of pyridazinones containing 6-amino-substituents

Cited by 24 publications

References 24 publications

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

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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