New Piperidin-۴-Amine Derivatives as Anti-HCV Inhibitors: A Structure-Based Approach Combining DFT, QSAR, and ADMET Analysis Targeting NS۵B Polymerase eceived

Hepatitis C virus is a major cause of severe liver disease, leading to complications such as cirrhosis, liver failure, hepatocellular carcinoma, and liver damage. 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 ۳۱ piperidine derivatives was performed. These molecules were computationally examined using a thorough in-silico technique that includes ۲D-۳D 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 B۳LYP version and ۶-۳۱G* 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 ۲D QSAR model (R² internal = ۰.۸۵۳۷, R² external = ۰.۶۹۷۹). Compound ۲۶ was the most promising candidate because of its remarkable binding affinity, which was demonstrated by the high molecular docking score of -۱۴۲.۲۴ 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 NS۵B polymerase (SCD۶ -۱۵۳.۷۴ kcal/mol). The newly discovered compounds have higher mole dock ratings than the FDA medicine Rib/Pig (-۱۱۱.۰۹۵ kcal/mol). According to the predicted drug-likeness and ADMET features, the most recently found compounds have a bioavailability value of ۰.۱۷, are easily synthesized in the wet laboratory (based on the synthetic accessibility value), and have favorable pharmacokinetic profiles. The developed molecule SCD۶, 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.

کلیدواژه ها:

Hepatitis C ، NS-۵B Polymerase ، ADMET properties ، Molecular docking ، QSAR ، Molecular Design ، Pharmacokinetics