QSAR, molecular docking, molecular dynamics and DFT-based design of novel Quinoline-2-yl (piperazin-1-yl) inhibitors of hepatitis C virus.

Liver cirrhosis and hepatocellular cancer are brought on by the hepatitis C virus (HCV). Since the virus's discovery, significant therapeutic advancements have been made. Recent studies have demonstrated the growing importance of plant compounds in the creation of novel, efficient, and reasonably priced anti-Hepatitis C virus therapies. The present study involved a thorough analysis of 35 Quinoline-2-yl (piperazin-1-yl) compounds. These compounds were computationally analyzed using in-silico methods like 2D-3D QSAR modeling and molecular docking, and their results were verified through the use of Density Functional Theory (DFT) calculations and ADMET characteristics assessment. The inhibitors were optimized using DFT based on a notion of B3LYP/6-31G* levels. The genetic function algorithm (GFA) was utilized to create the QSAR models. The best model was chosen based on its statistical fitness using the subsequent measurement parameters: R2trng = 0.8328, R2adj = 0.798036, Q2cv = 0.765153, and R2test = 0.6510 led to its selection and publication. A reliable 2D QSAR model was constructed and validated using an external validation test set, Y-randomization, variance inflation factor (VIF), mean effect (MF), and William's plot applicability domain (AD). The virtual screening of the compounds under study revealed that compound 29 was the top hit, with the highest mole dock score of -144.45 kcal/mol. A structure-based method was used to create six novel compounds with a higher affinity (SFBD3 -152.299 kcal/mol) for the NS5B polymerase. The food drug administration (FDA) drug Rib/Pig (-111.095 kcal/mol) has lower mole dock scores than the newly created compounds. Molecular dynamics (MD) simulations evaluated the binding stability and dynamic behavior of compounds 29 and SFD B3 with HCV NS5B polymerase (PDB ID: 3QK7) over 100 ns, using Desmond. Analyses of RMSD, RMSF, and hydrogen bonding revealed stable binding for both compounds. SFD B3 demonstrated superior stability (avg RMSD 1.92 Å, 2.91 H-bonds) compared to compound 29 (avg RMSD 2.32 Å, 0.94 H-bonds), indicating more favorable interaction dynamics within the NS5B active site. According to the synthetic accessibility score, the newly discovered compounds may be readily made in a wet lab, have excellent pharmacokinetic profiles, and have a bioavailability score of 0.55 based on the anticipated drug-likeness and ADMET properties. As potential Hepatitis C viral agents, the created molecule SFBD3, which is stable, has a higher affinity, and has the best pharmacokinetic characteristics, ought to be made in a wet lab.