Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: Structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides

Vicente, Javier de; Hendricks, R.; Smith, David B.; Fell, Jay B.; Fischer, John P.; Spencer, Stacey R.; Stengel, Peter J.; Mohr, Peter J.; Robinson, John; Blake, James F.; Hilgenkamp, Ramona; Yee, Calvin; Adjabeng, George M.; Elworthy, Todd R.; Li, Jim; Wang, Beihan; Bamberg, Joe T.; Harris, S.F.; Wong, Allen; Lévêque, Vincent; Nájera, Isabel; Pogam, Sophie Le; Rajyaguru, Sonal; Ao-Ieong, Gloria; Alexandrova, L. А.; Larrabee, Susan; Brandl, Michael; Briggs, Andrew J.; Sukhtankar, Sunil; Farrell, Robert

doi:10.1016/j.bmcl.2009.08.022

Cited by 31 publications

(12 citation statements)

References 13 publications

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“…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%

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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“…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%

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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“…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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“…The HCV RdRp and the three-dimensional structure of the experimental HCV inhibitor, compound 47, were obtained from the RSCB Protein Data Bank (PDB code: 3H5S and 3TYQ, respectively). 6,29 The apo system contains only the free enzyme. The bound system's protonation states were optimized, and then directly followed by the addition of hydrogen atoms using the Protein Preparation Wizard in Maestro (Schrödinger).…”

Section: System Preparationmentioning

confidence: 99%

Targeting HCV polymerase: a structural and dynamic perspective into the mechanism of selective covalent inhibition

Shunmugam

Soliman

2018

RSC Adv.

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Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: Structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides

Cited by 31 publications

References 13 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

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

Targeting HCV polymerase: a structural and dynamic perspective into the mechanism of selective covalent inhibition

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