Barakat Khaled H, Anwar-Mohamed Anwar, Tuszynski Jack A, Robins Morris J, Tyrrell D Lorne, Houghton Michael
Li Ka Shing Institute of Virology, University of Alberta , Edmonton, Alberta Canada.
J Chem Inf Model. 2015 Feb 23;55(2):362-73. doi: 10.1021/ci400631n. Epub 2014 Apr 14.
Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.
目前，许多能够选择性阻断丙型肝炎病毒（HCV）复制的直接作用抗病毒药物（DAAs）正在研发中。其中一种药物是达卡他韦，它是首个靶向NS5A病毒蛋白的抑制剂。尽管达卡他韦是目前已研发出的最有效的HCV抗病毒分子，但其结合位置和结合模式仍不清楚。该药物对耐药性突变的屏障较低，尤其是在1型病毒中，但它对其他基因型的疗效尚不清楚。我们利用最先进的建模技术并结合蓝色基因/Q的强大计算能力，确定了达卡他韦在NS5A中针对不同HCV基因型以及几种已报道的耐药突变的原子相互作用。所提出的模型首次揭示了达卡他韦的详细结合模式。它还提供了一种工具，便于设计第二代药物，这类药物可能产生较低的耐药性和/或对HCV具有更广泛的活性。
