Exploring of paritaprevir and glecaprevir resistance due to A156T mutation of HCV NS3/4A protease: molecular dynamics simulation study

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 similar to 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.

Automated summary

A156T mutation in HCV NS3/4A serine protease leads to drug resistance, and the newly approved drugs paritaprevir and glecaprevir exhibit different resistance profiles against this mutation. Molecular dynamics simulations and binding free energy calculations reveal that the binding affinities of paritaprevir and glecaprevir to A156T NS3/4A are significantly reduced compared to their wild-type complexes. The main contributions for the higher resistance of glecaprevir are the weak interactions with specific amino acids in NS3 protein and destabilized protein binding surface.