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

详细信息    查看全文

• 作者：Zhuyan Guo ; Andrew Prongay ; Xiao Tong ; Thierry Fischmann ; Stephane Bogen ; Francisco Velazquez ; Srikanth Venkatraman ; F. George Njoroge ; Vincent Madison
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：2
• 期：6
• 页码：1657 - 1663
• 全文大小：223K
• 年卷期：v.2,no.6(November 2006)
• ISSN：1549-9626

文摘

The effect of the resistance mutations A156T, D168V, and D168Q in HCV proteaseon the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluatedusing the free energy perturbation (FEP) approach. All the inhibitors are highly potent againstthe wild-type enzyme, but their activity was affected differently by the mutants. A156T reducedthe activity of SCH 503034, BILN-2061, and VX950 drastically (200-1000-fold) but that of SCH6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by eithermutation 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 theimportance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation.The results from FEP calculations compared well with experimental binding potencies within anerror of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to theatomic changes in the mutants.