Abstract

Hepatitis C virus (HCV) NS3/4A serine protease is a promising drug target for the discovery of anti-HCV drugs. However, its amino acid mutations, particularly A156T, commonly lead to rapid emergence of drug resistance. Paritaprevir and glecaprevir, the newly FDA-approved HCV drugs, exhibit distinct resistance profiles against the A156T mutation of HCV NS3/4A serine protease. To illustrate their different molecular resistance mechanisms, molecular dynamics simulations and binding free energy calculations were carried out on the two compounds complexed with both wild-type (WT) and A156T variants of HCV NS3/4A protease. QM/MM-GBSA-based binding free energy calculations revealed that the binding affinities of paritaprevir and glecaprevir towards A156T NS3/4A were significantly reduced by ∼4 kcal/mol with respect to their WT complexes, which were in line with the experimental resistance folds. Moreover, the relatively weak intermolecular interactions with amino acids such as H57, R155, and T156 of NS3 protein, the steric effect and the destabilized protein binding surface, which is caused by the loss of salt bridge between R123 and D168, are the main contributions for the higher fold-loss in potency of glecaprevir due to A156T mutation. An insight into the difference of molecular mechanism of drug resistance against the A156T substitution among the two classes of serine protease inhibitors could be useful for further optimization of new generation HCV NS3/4A inhibitors with enhanced inhibitory potency.

Communicated by Ramaswamy H. Sarma

摘要

丙型肝炎病毒（HCV）NS3 / 4A丝氨酸蛋白酶是发现抗HCV药物的有希望的药物靶标。但是，其氨基酸突变，特别是A156T，通常会导致耐药性的快速出现。FDA新批准的HCV药物Paritaprevir和glecaprevir对HCV NS3 / 4A丝氨酸蛋白酶的A156T突变表现出独特的耐药性。为了说明它们不同的分子抗性机制，对与HCV NS3 / 4A蛋白酶的野生型（WT）和A156T变体复合的两种化合物进行了分子动力学模拟和结合自由能计算。基于QM / MM-GBSA的结合自由能计算表明，相对于WT复合物，帕利他普韦和格列卡韦对A156T NS3 / 4A的结合亲和力显着降低了约4 kcal / mol，与实验电阻倍数一致。此外，主要的贡献是与NS3蛋白的H57，R155和T156等氨基酸的分子间相互作用相对较弱，空间效应和蛋白结合表面不稳定，这是由于R123和D168之间的盐桥丢失所致。因A156T突变导致格列卡韦效价的高倍损失。深入了解两类丝氨酸蛋白酶抑制剂之间针对A156T取代的耐药性分子机制的差异，可能有助于进一步优化具有增强抑制效能的新一代HCV NS3 / 4A抑制剂。R123和D168之间盐桥的丢失导致空间效应和不稳定的蛋白质结合表面，这是由于A156T突变导致格列卡韦效价更高的倍数损失的主要原因。深入了解两类丝氨酸蛋白酶抑制剂之间针对A156T取代的耐药性分子机制的差异，可能有助于进一步优化具有增强抑制效能的新一代HCV NS3 / 4A抑制剂。R123和D168之间盐桥的丢失导致空间效应和不稳定的蛋白质结合表面，这是由于A156T突变导致格列卡韦效价更高的倍数损失的主要原因。深入了解两类丝氨酸蛋白酶抑制剂之间针对A156T取代的耐药性分子机制的差异，可能有助于进一步优化具有增强抑制效能的新一代HCV NS3 / 4A抑制剂。

由Ramaswamy H.Sarma沟通