Designing cyclopentapeptide inhibitor of neuraminidase H5N1 virus through molecular and pharmacology simulations

Highly Pathogenic Avian Influenza (HPAI) H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase (NA) has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy (ΔG
_binding
). ADME-Tox prediction assay was conducted on the selected ligands. Intraand inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein: CLDRC and CIWRC. These two ligands have ΔG
_binding
values of -40.5854 and -39.9721 kcal/mol (1 kcal/mol = 4.18 kJ/mol). These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312K. At the end, both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.