Computational design of drug candidates for influenza A virus subtype H1N1 by inhibiting the viral neuraminidase-1 enzyme

Abstract

Influenza A virus subtype H1N1 causes severe infections in human respiratory system. This can lead to increased risk of mortality. Neuraminidase-1 has an important role It is critical to seek potential alternative treatments for H1N1 infections by inhibiting neuraminidase-1 enzyme. One of the viable options for inhibiting the activity of neuraminidase-1 is peptide drug design. In order to increase peptide stability, cyclization is necessary to prevent its digestion by protease enzyme. Cyclization of peptide ligands by formation of disulfide bridges is preferable for designing inhibitors of neuraminidase-1 because of their high activity and specificity. Here we designed ligands by using molecular docking, drug scan and dynamics computational methods. Based on our docking results, short polypeptides of cystein-arginine-methionine-tyrosine--proline-cysteine (CRMYPC) and cysteine-arginine-aspargine-phenylalanine-proline-cysteine (CRNFPC) have good residual interactions with the target and the binding energy DG binding of -31.7402 and -31.0144 kcal mol -1 , respectively. These values are much lower than those of the standards, and it means that both ligands are more accessible to ligand-receptor binding. Based on drug scan results, both of these ligands are neither mutagenic nor carcinogenic. They also show good oral bioavailability. Moreover, both ligands show relatively stable molecular dynamics progression of RMSD vs. time plot. However, based on our metods, the CRMYPC ligand has sufficient hydrogen bonding interactions with residues of the active side of neuraminidase-1 and can be therefore proposed as a potential inhibitor of neuraminidase-1.

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

“…Therefore, it could be guaranteed that the utilization of MOE as the backbone of this pipeline is indeed applicable in the computational approach of H5N1 drug design. This research group has conducted several computational works on cyclic hexapeptide and inferred that they could be developed as drug candidate for H1N1 [53] . Moreover, it has shown that cyclic pentapeptide could possibly be synthesized in the wet laboratory, in order to be developed as drug candidate for H1N1 [27] .…”

Screening Analogs of β-OG Pocket Binder as Fusion Inhibitor of Dengue Virus 2

“…This simulation consists of three steps: initialization, equilibration, and production. 32,33 The initialization process was conducted for 100 picoseconds at 300 K. The time needed to conduct equilibration process was determined according to initialization time when a ligand starts to form a stable complex with the DENV envelope. The production step took 10,000 picoseconds to run and involved a cooling stage for 10 picoseconds.…”

Safflomin A inhibits neuraminidase activity and influenza virus replication

“…These two ligands are predicted with no mutagencity or carcinogenicity and have good oral bioavailability. 33 We have also taken advantage of homology modeling to simulate the structure of H1N1 NA, the model structure of N1 was used to screen compounds of NPD database 34 for potential inhibitors. We found 34 of compounds with low affinity energy, among which, two natural compounds (ZINC02128091 and ZINC02098378) possessed the most favorable interaction energy.…”