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

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

“…Indeed, the 100-fold loss in potency of glecaprevir against gt3a was explained by the decreased stability of the active site conformation caused by modifications of the hydrogen-bonding pattern and VDW interactions, especially with the R123T mutation. In the A156T–glecaprevir complex, the Arg123–Asp168 ion-pair was completely lost, since the conformation of Arg123 was flipped and pointed toward the solvent-exposed protein surface, hence limiting the possibility to make a salt bridge interaction with Asp168 and thus causing weakened protein–ligand binding interactions …”

“…In the A156T−glecaprevir complex, the Arg123−Asp168 ion-pair was completely lost, since the conformation of Arg123 was flipped and pointed toward the solvent-exposed protein surface, hence limiting the possibility to make a salt bridge interaction with Asp168 and thus causing weakened protein−ligand binding interactions. 179 3.3.3. Structural Differences between P2−P4 of Second (Grazoprevir) and Third Generation (Voxilaprevir and Glecaprevir).…”