Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir. Issue 12 (12th October 2016)

• Record Type: Journal Article
• Authors: Meeprasert, Arthitaya; Hannongbua, Supot; Kungwan, Nawee; Rungrotmongkol, Thanyada
• Is Part Of: Molecular bioSystems. Volume 12:Issue 12(2016:Dec.)
• Page Start: 3666
• Page End: 3673
• Publication Date: 2016-10-12
• Subjects: Molecular biology -- Periodicals; Biochemistry -- Periodicals; 571.7405
• DOI: 10.1039/c6mb00610h
• Languages: English
• ISSNs: 1742-206X

Abstract

Abstract : Disrupted hydrogen bonding network in the extended S2 subsite lead to faldaprevir and danoprevir resistances. Abstract : Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80⋯R155⋯D168⋯R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10–15 kcal mol −1 and ∼4–9 kcal mol −1 relative to the wild-type complexes, respectively, which somewhat agrees with the experimental resistance folds.