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

Abstract

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 (G binding). ADME-Tox prediction assay was conducted on the selected ligands. Intra-and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. 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 G 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 312 K. At the end, both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.

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“…The entire experiment of this study was conducted by using our established in silico drug design research pipeline [33][34][35]. This research has been carried out by Personal Computer (PC) with Intel Core i3 540 @3.07 GHz Processor, 4GB Random Access Memory (RAM), ATI Radeon HD 4600 Series Graphic Card, and Windows 7 Professional Operating System.…”

Searching of Flavonoid Compounds as a New Antiviral for Sudan Ebolavirus Glycoprotein Using in Silico Methods

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