New Piperidin-4-Amine Derivatives as Anti-HCV Inhibitors: A Structure-Based Approach Combining DFT, QSAR, and ADMET Analysis Targeting NS5B Polymerase eceived: date; Accepted

Hepatitis C virus (HCV) is a major cause of severe liver disease, leading to complications such as cirrhosis, liver failure, and hepatocellular carcinoma, liver damage, and basic cancer of the liver (hepatocellular carcinoma). There have been major therapeutic advances since the virus's discovery. Recent research has shown that plant-derived compounds are increasingly valuable in the development of innovative, effective, and cost-effective anti-Hepatitis C Virus treatments. In the current work, a complete examination of 31 piperidin derivatives was performed, these molecules were computationally examined using a through in-silico technique that includes 2D-3D Quantitative Structure Activity Relationship (QSAR) simulation and docking of molecular structures, and their properties were confirmed using ADMET and Density Functional Theory (DFT) calculations. The anti-hepatitis C compounds have been optimized utilizing the DFT approach using the B3LYP version and 6-31G* basis set. The Genetic Function Algorithm (GFA) was utilized to develop five models. An externally verified test set, Y-randomization, variance inflation factor (VIF), mean effect (MF), and William's plot applicability domain (AD) were used to build and validate a credible 2D QSAR model (R2 internal = 0.8537, R2 external = 0.6979). Compound 26 was the most promising candidate because of its remarkable binding affinity, which was demonstrated by the high molecular docking score of -142.24 kcal/mol that was obtained from the virtual screening of the compounds under investigation. A structure-based approach created six new molecules with increased affinity for the NS5B polymerase (SCD6 -153.74 kcal/mol). The newly discovered compounds have higher mole dock ratings than the FDA medicine Rib/Pig (-111.095 kcal/mol). According to the predicted drug-likeness and ADMET features, the most recently found compounds have a bioavailability value of 0.17, are easily synthesized in the wet laboratory (based on the synthetic accessibility value), and have favorable pharmacokinetic profiles. The developed molecule SCD6, which is stable, has greater affinity, and has the best pharmacokinetic features, should be produced in the wet lab as prospective Hepatitis C viral agents.