Computer-aided molecular modeling and design studies of some N-(4-(dimethyl amino) phenyl)-4-methoxy-3-propionamidobenzamide derivatives as NS5B polymerase inhibitors

Abstract

Hepatitis C Virus (HCV) is a stealthy ailment, and most people are unaware they have it in the early stages. Insilco modeling was used to develop a model with high predictive power for N-(4-(dimethyl amino) phenyl)-4-methoxy-3-propionamidobenzamide inhibitors. The inhibitors were optimized using Density Functional Theory (DFT) based on a notion of B3LYP/6–31 G* 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 = 0.828181, R2adj = 0.800468, Q2cv = 0.734795, R2test = 0.7028, and LOF = 0.613985, led to its selection and publication. The model underwent additional assessments, including the Y-scrambling test, and applicability domain, and was considered to have statistical significance. The docking results demonstrate that compound 17 has the greatest inhibitory effect on NS5B-polymerase of any drug in the dataset. Using this compound as a template, novel anti-hepatitis C compounds were developed by including a few beneficial substituents. The docking results of the proposed compounds yielded a high MolDock score (−152.12), indicating effective binding to the target's active sites. Two comparable compounds (SBD4 and SBD3) were shown to be superior to the food drug administration (FDA) approved medication, revibirin/pegylated interferon. The chemicals were determined to be orally accessible after passing Lipinski's criteria, a drug similarity test. Furthermore, the synthesized compounds were found to have favorable pharmacokinetic (absorption, distribution, metabolism, excretion, and toxicity) properties. In conclusion, using the QSAR model, a model with excellent prediction power for certain Biaryl amide inhibitors was constructed. The model was validated and determined to have good internal and external assessment criteria. According to the docking results, compound 17 inhibits NS5B-polymerase the most out of the compounds in the dataset. Furthermore, the compounds' oral bioavailability met drug-like standards. The ultimate goal of this research is to contribute to the development of new therapeutic agents for the treatment of HCV infections, addressing the pressing need for effective antiviral medications.

Keywords

• Hepatitis C
• NS-5B Polymerase
• ADMET properties
• Molecular docking
• hepatitis C