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Shin W.-J.,Yonsei University | Nam K.-Y.,Drug Discovery Research Center | Kim N.-D.,HIGH-TECH | Kim S.-H.,Yonsei University | And 4 more authors.
Chemotherapy | Year: 2016

Background: The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. Methods: An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. Results: The hit compound (BMD-2601505) was effective [50% effective concentration (EC50) of 60-70 μM] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC50 of 22-37 μM) against the influenza viruses tested. Conclusion: We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates. © 2016 S. Karger AG, Basel.

Owen M.C.,Julich Research Center | Strodel B.,Julich Research Center | Strodel B.,Heinrich Heine University Dusseldorf | Csizmadia I.G.,University of Toronto | And 4 more authors.
Journal of Physical Chemistry B | Year: 2016

We examined the effects of Cα-centered radical formation on the stability of a model helical peptide, N-Ac-KK(AL)10KK-NH2. Three, 100 ns molecular dynamics simulations using the OPLS-AA force field were carried out on each α-helical peptide in six distinct binary TIP4P water/2,2,2-trifluoroethanol (TFE) mixtures. The α-helicity was at a maximum in 20% TFE, which was inversely proportional to the number of H-bonds between water molecules and the peptide backbone. The radial distribution of TFE around the peptide backbone was highest in 20% TFE, which enhanced helix stability. The Cα-centered radical initiated the formation of a turn within 5 ns, which was a smaller kink at high TFE concentrations, and a loop at lower TFE concentrations. The highest helicity of the peptide radical was measured in 100% TFE. The formation of hydrogen bonds between the peptide backbone and water destabilized the helix, whereas the clustering of TFE molecules around the radical center stabilized the helix. Following radical termination, the once helical structure converted to a β-sheet rich state in 100% water only, and this transition did not occur in the nonradical control peptide. This study gives evidence on how the formation of peptide radicals can initiate α-helical to β-sheet transitions under oxidative stress conditions. © 2016 American Chemical Society.

Owen M.C.,Semmelweis University | Owen M.C.,University of Szeged | Owen M.C.,Global Institute of Computational Molecular and Materials Science | Owen M.C.,Drug Discovery Research Center | And 11 more authors.
Journal of Chemical Theory and Computation | Year: 2012

Recent studies using ab initio calculations have shown that C α-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of C α-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the C α-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the C α-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the C α-containing residue (Alr) are preferred and these conformations increase the formation of γ-, α-, and π-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 3 10-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the C α of peptide and protein residues. © 2012 American Chemical Society.

Owen M.C.,University of Toronto | Owen M.C.,University of Szeged | Owen M.C.,NRC Steacie Institute for Molecular Sciences | Owen M.C.,Drug Discovery Research Center | And 8 more authors.
Journal of Physical Chemistry B | Year: 2012

To determine if •OH can initiate the unfolding of an amino acid residue, the elementary reaction coordinates of H abstraction by •OH different conformations (βL, γL, γD, αL, and αD) of Gly and Ala dimethyl amides were computed using first-principles quantum computations. The MPWKCIS1K/6-311++G(3df,2p)// BHandHLYP/6-311+G(d,p) level of theory was selected after different combinations of functionals and basis sets were compared. The structures of Gly and Ala in the elementary reaction steps were compared to the conformers of the Gly, Gly•, Ala, and Ala• structures in the absence of •OH/H2O, which were identified by optimizing the minima of the respective potential energy surfaces. A dramatic change in conformation is observed in the Gly and Ala conformers after conversion to Gly• and Ala•, respectively, and this change can be monitored along the minimal energy pathway. The βL conformer of Gly (-0.3 kJ mol-1) and Ala (-1.6 kJ mol-1) form the lowest-lying transition states in the reaction with •OH, whereas the side chain of Ala strongly destabilizes the α conformers compared to the γ conformers, which could cause the lower reactivity shown in Ala. This effect shown in Ala could affect the abstraction of hydrogen from Ala and the other chiral amino acid residues in the helices. The energy of subsequent hydrogen abstraction reactions between Ala• and Gly • and H2O2 remains approximately 90 kJ mol-1 below the entrance level of the •OH reaction, indicating that the •OH radical can initiate an α to β transition in an amino acid residue if a molecule such as H 2O2 can provide the hydrogen atom necessary to re-form Gly and Ala. This work delineates the mechanism of the rapid •OH- initiated unfolding of peptides and proteins which has been proposed in Alzheimer's and other peptide misfolding diseases involving amyloidogenic peptides. © 2011 American Chemical Society.

Fiser B.,University of Szeged | Fiser B.,Drug Discovery Research Center | Szori M.,University of Szeged | Szori M.,Drug Discovery Research Center | And 9 more authors.
Journal of Physical Chemistry B | Year: 2011

All possible X-H (where X can be C, N, O or S) bond dissociation energies (BDEs) of glutathione (γ-l-glutamyl-l-cysteinyl-glycine, GSH) and its fragments have been calculated by first principle methods, and the antioxidant potential of GSH was revealed to be higher than expected in earlier studies. Electron delocalization was found to have an important influence on the antioxidant potential. All structures were optimized and their harmonic vibrational frequencies were calculated in the gas phase at the B3LYP/6-31G(d) level of theory. Solvent effects were taken into account for optimizations at the same level of theory by applying the conductor-like polarizable continuum model (CPCM). Hydrogen cleavage from glutathione proved that the G3MP2B3 composite method provides results consistent with the experimental values for bond dissociation enthalpies (DH298) of S-H, O-H, C-H, and N-H bonds. In order to replace the G3MP2B3 energies with accurate single point calculations, six density functionals, namely, MPWKCIS, MPWKCIS1K, M06, TPSS1KCIS, TPSSh, and B3LYP, were tested against G3MP2B3 for obtaining accurate bond dissociation energies. The MPWKCIS1K/6-311++G(3df,2p)//B3LYP/6-31G(d) level of theory provides the best correlation with the G3MP2B3 method for BDEs in both phases, and therefore, it is recommended for similar calculations. Gas phase results showed that the O-H bond was the weakest, while in aqueous phase the N-H bond in the ammonium group proved to have the smallest BDE value in the studied system. In both cases, the cleavage of the X-H bond was followed by decarboxylation which was responsible for the energetic preference of these processes over the S-H dissociation, which was regarded as the most favorable one until now. The calculated BDE values showed that in aqueous phase the most preferred H-abstraction site is at the weakest N-H bond (BDEaq = 349.3 kJ mol-1) in the glutamine fragment near the α-carbon. In water, the formation of N-centered radicals compared to S-centered ones (BDEaq = 351.7 kJ mol-1) is more endothermic by 2.54 kJ mol-1, due to decarboxylation. Hydrogen dissociation energies from the α-carbons are also comparable in energy with those of the thiol hydrogen, within computational error. The higher stability of the radicals-except the S-centered ones-is due to various degrees of electron delocalization. In aqueous phase, four quasi-equivalent stable radical centers (the α-carbons, the N-centered radical of the NH2 group, and the S-centered radical) were found which provide the antioxidant behavior of glutathione. © 2011 American Chemical Society.

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