Structural Modeling of New Polymorphism Clusters of HCV Polymerase Isolated from Direct‐Acting Antiviral Naïve Patients: Focus on Dasabuvir and Setrobuvir Binding Affinity.

Management of Hepatitis C virus infection changed after the development of direct‐acting antiviral agents, including NS5B polymerase inhibitors. However, the presence of non‐synonymous substitutions could lead to therapy failure. Herein, we analyzed novel polymorphism clusters in NS5B polymerase from Hepatitis C virus (HCV) subtype 1b isolates of direct‐acting antivirals (DAAs) naïve patients by Sanger population sequencing. By means of computational approaches, we investigated the impact of these polymorphisms on the apo‐polymerase stability and on the binding affinity of dasabuvir and setrobuvir. Our thermodynamic and structural analysis highlighted that some mutational patterns could enhance or reduce the drug's affinity if compared to the wild‐type complexes and allowed us to well characterize the binding mode of the known drugs into the NS5B binding pocket. Our computational findings agreed with dasabuvir and setrobuvir in vitro reduced binding affinities against C316N mutant and could be useful in guiding the therapeutic approaches in presence of specific natural polymorphisms on HCV polymerase. 3D representation of the superposed structures of WT (blue cartoon) and C316N (red cartoon) NS5B models obtained from Molecular Dynamics simulations. By comparing the wild‐type and the mutated proteins, structural differences around the residue 316 became more clear in both forms. The morphological information, supported by chemical and steric differences, allows us to better comprehend the enzymatic adaptation which is translating in diverse drug activities. The enzyme is reported as grey carbon surface. [ABSTRACT FROM AUTHOR]