Ahmed Safwat El-Azazy, Hossam Sabry, Mohammed Ashraf, Ahmed Ehab Shabrawy, Ahmed Fawzy, Muhammed Ismail, Maria Attallah and Mahmoud Salama Ahmed
Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City Cairo-Suez Desert Road Cairo, Egypt
Hepatitis-C virus (HCV) is a blood-borne viral infection caused by single-stranded RNA virus. HCV genotype 4 is prevalent in Egypt, Middle East, and Africa. Inhibition of RNA polymerase enzyme is a novel trend in the pharmaceutical industry using non-nucleoside analogs. IDX375 is a newly discovered NS5B polymerase inhibitor, where it is still in the clinical trials. Hence, a virtual library comprised of 40 ligands following systematic structural modifications was designed. This was followed by energy minimization using MMFF94. The whole library was screened initially for their physico-chemical properties; such as molecular weight, lipophilicity, polar surface area, number of hydrogen bond donors and acceptors via FILTER application. The filtered analogs were docked along with NS5B polymerase enzyme co-crystallized with IDX375 (PDB ID: 4EAW) using OpenEye molecular modeling software and further validated using Auto Dock Vina Tools. Twelve ligands showed better binding affinity ranged from -10.20 Kcal/mol -9.10 Kcal/mol, compared to IDX-375 (ΔG= -8.00 Kcal/mol). The findings revealed the potential of substituting of tertiary-butyl group at C-33 with systematic ring variation modification, ending with cyclohexane ring, showing better hydrophobic interaction.