Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Ruebsam, Frank; Webber, S. E.; Tran, Martin T.; Tran, Chinh V.; Murphy, Douglas E.; Zhao, Jingjing; Dragovich, Peter S.; Kim, Sun Hee; Li, Lian‐Sheng; Zhou, Yang; Han, Qinghong; Kissinger, Charles R.; Showalter, Richard E.; Lardy, Matthew; Shah, Anup; Tsan, Mei; Patel, Rupal; LeBrun, Laurie A.; Kamran, Ruhi; Sergeeva, Maria V.; Bartkowski, Darian M.; Nolan, Thomas G.; Norris, Daniel A.; Kirkovsky, Leo

doi:10.1016/j.bmcl.2008.04.066

Cited by 36 publications

(19 citation statements)

References 32 publications

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“…Fig. 1 shows the structures of each ligand and their corresponding IC 50 values (19,(21)(22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

“…This enzyme could be trapped in the more open state in their work due to crystal-packing effects. In addition, as noted in Materials and Methods, the PDB: 2BRL structure used for 1:POO contains a loop with missing residues (22,(29)(30)(31)(32)(33)(34). The coordinates of these residues were inserted by employing the corresponding coordinates from the PDB: 2WHO structure.…”

Section: Thumb Site I (Nni-1) Inhibitors Reduce Enzyme Stabilitymentioning

confidence: 99%

“…Crystal structures of the genotype 1b HCV RNA polymerase (NS5B) from the Protein Data Bank (PDB) with the following PDB codes were used as the initial coordinates (location of the allosteric binding site is in parentheses): PDB: 2BRL (NNI-1), PDB: 2HAI (NNI-2), PDB: 2WHO (NNI-2), PDB: 3CO9 (NNI-3), and PDB: 3HHK (NNI-3) (19,(21)(22)(23)(24). The PDB: 2BRL crystal structure did not contain residues 22-35 (the D1 loop near the ligand binding site) or 148-152 (part of the D2 loop).…”

Section: Simulation Conditionsmentioning

confidence: 99%

“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). We will refer to NNI-1 and -2 as ''thumb inhibitors'' while NNI-3 and -4 will be referred to as ''palm inhibitors''.…”

Section: Introductionmentioning

confidence: 99%

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Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase

Davis

Brown

Thorpe

2015

Biophysical Journal

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The RNA-dependent RNA polymerase from the Hepatitis C Virus (gene product NS5B) is a validated drug target because of its critical role in genome replication. There are at least four distinct allosteric sites on the polymerase to which several small molecule inhibitors bind. In addition, numerous crystal structures have been solved with different allosteric inhibitors bound to the polymerase. However, the molecular mechanisms by which these small molecules inhibit the enzyme have not been fully elucidated. There is evidence that allosteric inhibitors alter the intrinsic motions and distribution of conformations sampled by the enzyme. In this study we use molecular dynamics simulations to understand the structural and dynamic changes that result when inhibitors are bound at three different allosteric binding sites on the enzyme. We observe that ligand binding at each site alters the structure and dynamics of NS5B in a distinct manner. Nonetheless, our studies also highlight commonalities in the mechanisms of action of the different inhibitors. Each inhibitor alters the conformational states sampled by the enzyme, either by rigidifying the enzyme and preventing transitions between functional conformational states or by destabilizing the enzyme and preventing functionally relevant conformations from being adequately sampled. By illuminating the molecular mechanisms of allosteric inhibition, these studies delineate the intrinsic functional properties of the enzyme and pave the way for designing novel and more effective polymerase inhibitors. This information may also be important to understand how allosteric regulation occurs in related viral polymerases and other enzymes.

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“…Fig. 1 shows the structures of each ligand and their corresponding IC 50 values (19,(21)(22)(23)(24).…”

Section: Resultsmentioning

confidence: 99%

Section: Thumb Site I (Nni-1) Inhibitors Reduce Enzyme Stabilitymentioning

confidence: 99%

Section: Simulation Conditionsmentioning

confidence: 99%

“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). We will refer to NNI-1 and -2 as ''thumb inhibitors'' while NNI-3 and -4 will be referred to as ''palm inhibitors''.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase

Davis

Brown

Thorpe

2015

Biophysical Journal

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“…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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Synthesis of Tetrahydropyridazines by a Metal–Carbene‐Directed Enantioselective Vinylogous NH Insertion/Lewis Acid‐Catalyzed Diastereoselective Mannich Addition

Zavalij

Doyle

2012

Angewandte Chemie

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Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Cited by 36 publications

References 32 publications

Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase

Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase

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

Synthesis of Tetrahydropyridazines by a Metal–Carbene‐Directed Enantioselective Vinylogous NH Insertion/Lewis Acid‐Catalyzed Diastereoselective Mannich Addition

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