Studies of the Symmetric Binding Mode of Daclatasvir and Analogs Using a New Homology Model of HCV NS5A GT-4a

Abstract The Hepatitis C virus (HCV) genotype 4a (GT-4a) is widespread in Egypt. Despite its high resistance, it received insufficient scientific attention. Since the crystal structure of full-length HCV NS5A has not yet been resolved, and the 3D structure of NS5A in complex with direct-acting antivirals (DAA) is a point of controversy, as seven groups present different interaction models to elucidate the NS5A binding site, there is currently no consensus on the NS5A binding site. Hence, homology modeling was used to construct a 3D model of HCV NS5A GT -4a, and dynamic simulation was used to validate the generated model. Intriguingly, the constructed model shows a new orientation of the AH relative to the domain I (D-I). Following this, docking was carried out for the approved NS5A inhibitors to understand their mechanism of action. The suggested model reveals for the first time the exact binding mode of daclatasvir and its analogs to HCV NS5A GT -4a. It also facilitates the design of novel NS5A-directed drugs, which may confer less resistance and/or a broader spectrum of efficacy against HCV.