title: Computational Study of the Effects of Mutations A156T, D168V, and D168Q on the Binding of HCV Protease Inhibitors.
abstract: The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the activity of SCH 503034, BILN-2061, and VX950 drastically (200-1000-fold) but that of SCH 6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by either mutation D168V or D168Q, but these mutations conferred a high level of resistance to BILN-2061. Comparison of BILN-2061 with its acyclic analogue compound 1 emphasized the importance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation. The results from FEP calculations compared well with experimental binding potencies within an error of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to the atomic changes in the mutants.
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fischmann
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Stephane
authors.initials: S
authors.lastname: Bogen
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.affiliation: Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison