Ligand-induced changes in hepatitis C virus NS5B polymerase structure

Rigat, Karen; Wang, Yi; Hudyma, Thomas W.; Ding, Min; Zheng, Xiaofan; Gentles, Robert G.; Beno, Brett R.; Gao, Min; Roberts, Susan B.

doi:10.1016/j.antiviral.2010.08.014

Cited by 27 publications

(27 citation statements)

References 33 publications

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“…Previous results suggested that the L30S variant is an enzyme with fingers and the thumb in a more open conformation (41,42,48). In our binding studies, the inhibitor on-and off-rates for the L30S polymerase The kinetic data suggest that a more exposed pocket is available for the initial binding of BMS-791325 to L30S.…”

mentioning

confidence: 50%

“…The substitution of serine for leucine at position 30 (L30S) reduces the affinity of the ⌬1 loop for the hydrophobic thumb pocket and weakens the finger-thumb interaction (42). The L30S variant has dramatically decreased polymerase activity, suggesting that the finger and thumb interaction is important for replication activity (41,42). Substitutions at Leu-30 have not been observed after inhibitor selection in the replicon system, but characterization of the L30S variant has been reported (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…1). The substitution of serine for leucine at position 30 (L30S) reduces the affinity of the ⌬1 loop for the hydrophobic thumb pocket and weakens the finger-thumb interaction (42). The L30S variant has dramatically decreased polymerase activity, suggesting that the finger and thumb interaction is important for replication activity (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…The L30S variant has dramatically decreased polymerase activity, suggesting that the finger and thumb interaction is important for replication activity (41,42). Substitutions at Leu-30 have not been observed after inhibitor selection in the replicon system, but characterization of the L30S variant has been reported (41,42). Although the overall activity of L30S polymerase is reduced (ϳ100-fold) compared with WT (42), inhibition of the variant by BMS-791325 (IC 50 ϭ 0.7 Ϯ 0.2 nM) is equal to the inhibition of WT polymerase (IC 50 ϭ 0.7 Ϯ 0.3 nM) when the inhibitor-NS5B interaction is allowed to reach equilibrium before polymerization is initiated ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…The specific activity (cpm incorporated/ng of protein) of the L30S polymerase is reduced (ϳ100-fold) compared with WT (41,42), but the potency of BMS-791325 on L30S, after preincubation, is equal to that on WT polymerase. The preincubation time required to achieve maximum inhibition of L30S appears to be shorter than that for WT (similar IC 50 values for L30S after 1-, 5-, and 24-h preincubation).…”

Section: Assaymentioning

confidence: 99%

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Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Rigat

Lü

Wang

et al. 2014

Journal of Biological Chemistry

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Background: BMS-791325, a non-nucleoside inhibitor of HCV NS5B, has robust clinical efficacy. Results: Biochemical and biophysical methods revealed a non-competitive time-dependent inhibition mechanism and permitted complete parameterization of inhibitor binding kinetics. Conclusion: Thumb and finger variants affect BMS-791325 association rates. Significance: The impact of NS5B variants on BMS-791325 binding provides insight into the basis of inhibitor resistance and the process of replication complex formation.

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mentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Assaymentioning

confidence: 99%

See 3 more Smart Citations

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Rigat

Lü

Wang

et al. 2014

Journal of Biological Chemistry

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Analysis of the Resistance of Hepatitis C Virus NS5B Polymerase Inhibitors via Docking and Molecular Dynamics Simulation

Uengwetwanit

Robaa

Sippl

2015

Molecular Informatics

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In this work, we examined how known single point mutations (P495S, P495L, P495A, P496A, P496S and V499A) in Hepatitis C virus NS5B polymerase influence the binding of benzimidazole-5-carboxamide derivatives which are potent NS5B inhibitors. Docking and molecular dynamics simulations were performed to analyze the binding of the inhibitors to the wild-type and mutant enzymes. Binding free energy calculations (MM-GB/SA method) and analyzing the decomposed binding free energy of individual residues were able to explain the differences in the inhibitory potency of the compounds at wild-type and mutant enzymes and hence account for the appearance of resistance of mutant enzymes to the studied inhibitors. The obtained results were found to be in agreement with the known experimental data.

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Hepatitis C RNA-dependent RNA polymerase inhibitors: A review of structure–activity and resistance relationships; different scaffolds and mutations

Mayhoub

2012

Bioorganic & Medicinal Chemistry

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Ligand-induced changes in hepatitis C virus NS5B polymerase structure

Cited by 27 publications

References 33 publications

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Analysis of the Resistance of Hepatitis C Virus NS5B Polymerase Inhibitors via Docking and Molecular Dynamics Simulation

Hepatitis C RNA-dependent RNA polymerase inhibitors: A review of structure–activity and resistance relationships; different scaffolds and mutations

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