Structure-based design, drug-likeness, and pharmacokinetic studies of novel substituted pyrimidine derivatives as potent HCV NS3/A4 protease inhibitors

Abstract

Hepatitis C virus (HCV) infection promotes death rates all over the world. HCV infection is considered a drastic health problem over the world, affecting up to 3% of the population each year. Since NS3/A4 helicase is crucial for HCV replication, this protein was selected as the target for in-silico screening for the design of novel viral entry inhibitors. The finding of valuable information that will aid in the discovery of unique active molecules that may be used to cure HCV infection and subsequently give medically effective therapy is undoubtedly a top global health priority. The PubChem drug repository of publicly available compounds was tested in silico using the enzyme-established RNA binding pronged, yielding 51 substances that were then evaluated for drug likeness, ADMET profile, and synthetic accessibility. Compound 15 was selected as the best hit for designing novel potent HCV NS3/A4 protease inhibitors by structural modification. Most of the molecules designed were proven to disrupt the enzyme by entirely occupying the binding sites of the receptor. The proposed molecule 15f outperformed Voxilaprevir, the FDA-approved NS3/A4 protease inhibitor, with a binding energy of −37.84 kcal/mol compared to −31.86 kcal/mol for Voxilaprevir. Moreover, the ADMET analysis of the proposed molecule (15f) shows higher overall quality with a drug score of 0.57, especially in comparison to Voxilaprevir, which has a drug score of 0.06.