Identification of novel compounds against an R294K substitution of influenza A (H7N9) virus using ensemble based drug virtual screening.

Influenza virus H7N9 foremost emerged in China in 2013 and killed hundreds of people in Asia since they possessed all mutations that enable them to resist to all existing influenza drugs, resulting in high mortality to human. In the effort to identify novel inhibitors combat resistant strains of influenza virus H7N9; we performed virtual screening targeting the Neuraminidase (NA) protein against natural compounds of traditional Chinese medicine database (TCM) and ZINC natural products. Compounds expressed high binding affinity to the target protein was then evaluated for molecular properties to determine drug-like molecules. 4 compounds showed their binding energy less than -11 Kcal/mol were selected for molecular dynamics (MD) simulation to capture intermolecular interactions of ligand-protein complexes. The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method was utilized to estimate binding free energy of the complex. In term of stability, NA-7181 (IUPAC namely {9-Hydroxy-10-[3-(trifluoromrthyl) cyclohexyl]-4.8-diazatricyclo [6.4.0.02,6]dodec-4-yl}(perhydro-1H-inden-5-yl)formaldehyde) achieved stable conformation after 20 ns and 27 ns for ligand and protein root mean square deviation, respectively. In term of binding free energy, 7181 gave the negative value of -30.031 (KJ/mol) indicating the compound obtained a favourable state in the active site of the protein.

Hyperbaric oxygen therapy reduces the severity of ischaemia, preservation and reperfusion injury in a rat model of liver transplantation.

BACKGROUND: Approaches to increase organ availability for orthotopic liver transplantation (OLT) often result in the procurement of marginal livers that are more susceptible to ischaemia, preservation and reperfusion injury (IPRI). METHODS: The effects of post-OLT hyperbaric oxygen (HBO) therapy on IPRI in a syngeneic rat OLT model were examined at various time-points. The effects of IPRI and HBO on hepatocyte necrosis, apoptosis, proliferation, and sinusoidal morphology and ultrastructure were assessed. RESULTS: Post-OLT HBO therapy significantly reduced the severity of IPRI; both apoptosis [at 12 h: 6.4 ± 0.4% in controls vs. 1.6 ± 0.7% in the HBO treatment group (p < 0.001); at 48 h: 2.4 ± 0.2% in controls vs. 0.4 ± 0.1% in the HBO treatment group (p < 0.001)] and necrosis [at 12 h: 18.7 ± 1.8% in controls vs. 2.4 ± 0.4% in the HBO treatment group (p < 0.001); at 48 h: 8.5 ± 1.3% in controls vs. 3.4 ± 0.9% in the HBO treatment group (P= 0.019)] were decreased. Serum alanine transaminase was reduced [at 12 h: 1068 ± 920 IU/l in controls vs. 370 ± 63 IU/l in the HBO treatment group (P= 0.030); at 48 h: 573 ± 261 IU/l in controls vs. 160 ± 10 IU/l in the HBO treatment group (P= 0.029)]. Treatment with HBO also promoted liver regeneration [proliferation at 12 h: 4.5 ± 0.1% in controls vs. 1.0 ± 0.3% in the HBO treatment group (p < 0.001); at 48 h: 8.6 ± 0.7% in controls vs. 2.9 ± 0.2% in the HBO treatment group (p < 0.01)] and improved sinusoidal diameter and microvascular density index. CONCLUSIONS: Hyperbaric oxygen therapy has persistent positive effects post-OLT that may potentially transfer into clinical practice.