In-silico Pharmacokinetic and Affinity Studies of Piperazine/Morpholine Substituted Quinolines in Complex with GAK as Promising Anti-HCV Agent

Abstract

Piperazine/morpholine derivatives of quinoline substituted at positions C-3, C-6 and C-8 has been previously prepared by SNAr reactions of 3,6,8-tribromoquinoline (1) under microwave or conventional heating reaction conditions. In this study, we evaluated binding interactions between the piperazine/morpholine substituted quinolines and its highly-likely receptor, Cyclin G associated kinase (GAK) involved in hepatitis C virus (HCV) entry into host cells, via docking, molecular dynamics (MD), thermodynamic and pharmacokinetics computations in order to select a possible lead compound, which may be used for lead-optimization in our future studies to develop novel drug candidates against HCV infections. 372 nsec MD simulations followed by MM-PBSA thermodynamic computations revealed that compound 23 ([Formula: see text]= 0.08[Formula: see text]nM) possesses the greatest potential to inhibit GAK. Pharmacokinetics computations suggest that compound 23 is a drug-like molecule as it conforms to the Lipinski filter. We determined that compound 23 could be a lead-like molecule for peripheric and cerebral HCV infections.