The Inhibitory Potential of 2′-dihalo Ribonucleotides against HCV: Molecular Docking, Molecular Simulations, MM-BPSA, and DFT Studies

Sofosbuvir is the first approved direct-acting antiviral (DAA) agent that inhibits the HCV NS5B polymerase, resulting in chain termination. The molecular models of the 2 '-dihalo ribonucleotides used were based on experimental biological studies of HCV polymerase inhibitors. They were modeled within HCV GT1a and GT1b to understand the structure-activity relationship (SAR) and the binding interaction of the halogen atoms at the active site of NS5B polymerase using different computational approaches. The outputs of the molecular docking studies indicated the correct binding mode of the tested compounds against the active sites in target receptors, exhibiting good binding free energies. Interestingly, the change in the substitution at the ribose sugar was found to produce a mild effect on the binding mode. In detail, increasing the hydrophobicity of the substituted moieties resulted in a better binding affinity. Furthermore, in silico ADMET investigation implied the general drug likeness of the examined derivatives. Specifically, good oral absorptions, no BBB penetration, and no CYP4502D6 inhibitions were expected. Likely, the in silico toxicity studies against several animal models showed no carcinogenicity and high predicted TD50 values. The DFT studies exhibited a bioisosteric effect between the substituents at the 2 '-position and the possible steric clash between 2 '-substituted nucleoside analogs and the active site in the target enzyme. Finally, compound 6 was subjected to several molecular dynamics (MD) simulations and MM-PBSA studies to examine the protein-ligand dynamic and energetic stability.

Automated summary

This study investigated the interaction between Sofosbuvir and HCV NS5B polymerase using molecular modeling and computational methods. The results demonstrated that the tested compounds correctly bind to the active sites with good binding affinities. The substituents had a mild effect on the binding mode, with increased hydrophobicity leading to better binding affinities. Drug likeness and toxicity studies suggested that the examined derivatives have potential as safe drugs. Molecular dynamics simulations and energy stability studies further confirmed the stability of the compound.