Computational Study of the Effects of Mutations A156T, D168V, and D168Q on the Binding of HCV Protease Inhibitors

Zhuyan Guo; Andrew Prongay; Xiao Tong; Thierry Fischmann; Stephane Bogen; Francisco Velazquez; Srikanth Venkatraman; F George Njoroge; Vincent Madison

doi:10.1021/ct600151y

Computational Study of the Effects of Mutations A156T, D168V, and D168Q on the Binding of HCV Protease Inhibitors

J Chem Theory Comput. 2006 Nov;2(6):1657-63. doi: 10.1021/ct600151y.

Authors

Zhuyan Guo¹, Andrew Prongay¹, Xiao Tong¹, Thierry Fischmann¹, Stephane Bogen¹, Francisco Velazquez¹, Srikanth Venkatraman¹, F George Njoroge¹, Vincent Madison¹

Affiliation

¹ Departments of Structural Chemistry, Medicinal Chemistry, and Antiviral Therapy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.

PMID: 26627036
DOI: 10.1021/ct600151y

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.