Molecular dynamics and docking reveal the potency of novel GTP derivatives against RNA dependent RNA polymerase of genotype 4a HCV

Abstract

Aim: To work on Hepatitis C Virus (HCV), one of the major causes of liver cirrhosis and hepatocellular carcinoma, polymerase of genotype 4a that have no solved structures deposited in the protein data bank (PDB) yet. Understanding the dynamics and testing some novel inhibitors are also covered.

Materials and methods: Molecular Dynamics Simulation (MDS) is performed for a period of 1 μs on comparatively modeled then validated NS5b of subtype 4a. Following MDS analysis, molecular docking is performed to test the inhibitory performance of eight novels suggested guanosine derivatives using 181 different conformations of the protein model gathered during the MDS run after the equilibration period.

Key findings: The results yield that the eight modified, at position 2', GTP derivatives (fluorine, Hydroxyl, and sulphonyl oxydanyl) have binding energies comparable to the parent molecule, GTP. Besides, the eight suggested compounds have lower binding energies (and hence better in binding) compared to sofosbuvir (a drug approved by FDA in 2013 against HCV) and ribavirin (a wide range acting antiviral drug used before against HCV).

Significance: Combined molecular dynamics and molecular docking are able to test the hypothesis of HCV polymerase dynamics doesn't affect the nucleotides (or nucleotide inhibitors) binding to its active site. Despite the reported highly dynamic subtype 4a of HCV; all the nucleotide inhibitors under the study are able to, tightly, bind to NS5b of genotype 4a. This behavior is reported before for the Zika virus polymerase, as well.

Keywords: HCV genotype 4a; Molecular dynamics simulation; Molecular modeling; Nucleotide inhibitors; Polymerase; Protein-ligand docking.