We have probed capability of small CID 9998128 compound as a potential multi-target drug for the ... more We have probed capability of small CID 9998128 compound as a potential multi-target drug for the Alzheimer's disease (AD) using in silico and in vitro experiments. By all-atom simulation and MM-PBSA method we have demonstrated that this compound strongly binds to both amyloid beta 42 (Aβ) fibrils and β-secretase and the van der Waals interaction is dominating over the electrostatic interaction in binding affinity. A detailed analysis at the atomic level revealed that indazole in CID 99998128 structure made a major contribution to instability of all studied complexes. In vitro experiments have shown that CID 9998128 inhibits the Aβ amyloid fibrillization and is capable to clear Aβ fibrils. Moreover, compound dose-dependently decreases β-site amyloid precursor protein cleaving enzyme (1BACE-1) activity with EC value in micromolar range. Thus our study has revealed that CID 9998128 is a good candidate for AD treatment through preventing production of Aβ peptides and degrading their...
International Journal of Biological Macromolecules, 2015
We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the the... more We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the thermal stability and fibrillation of human insulin. Thermostability of human insulin used differential scanning calorimetry (DSC), which showed two phase-transitions for insulin at 60 and 82°C. After adding dendrimers at 0.6μmol/l, the first peaks disappeared and the second peaks were higher. We posited that, in the presence of dendrimers, the dimers in the solution were transformed into hexamers. The effect of dendrimers on insulin fibrillation was monitored by measuring ThT fluorescence, and visualization of insulin fibrils by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The effect of PAMAM dendrimers on insulin fibrillation was strongly dependent on the dendrimers generation and dendrimer:protein ratio.
It is well known that misfolded peptides/proteins can play a role in processes of normal ageing a... more It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer's disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer's disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer's disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer's disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer's ...
Cytochrome c oxidase binds protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) with high... more Cytochrome c oxidase binds protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) with high affinity. There are 1.46 high-affinity binding sites per cytochrome c oxidase for CCCP with dissociation constant 2.7 x 10(-7) mol/l. The bond between the CCCP and cytochrome c oxidase accomplishes through the group on cytochrome c oxidase with pKa 6.64 and is based on the electrostatic interaction. Interaction of CCCP with low-affinity binding sites of cytochrome c oxidase induces the shift of the anion CCCP spectrum to UV-region. The similar effect is characteristic for CCCP interaction with protons. Lipophilic non-dissociated derivative NCH3CCP is not binding to cytochrome c oxidase.
We have probed capability of small CID 9998128 compound as a potential multi-target drug for the ... more We have probed capability of small CID 9998128 compound as a potential multi-target drug for the Alzheimer's disease (AD) using in silico and in vitro experiments. By all-atom simulation and MM-PBSA method we have demonstrated that this compound strongly binds to both amyloid beta 42 (Aβ) fibrils and β-secretase and the van der Waals interaction is dominating over the electrostatic interaction in binding affinity. A detailed analysis at the atomic level revealed that indazole in CID 99998128 structure made a major contribution to instability of all studied complexes. In vitro experiments have shown that CID 9998128 inhibits the Aβ amyloid fibrillization and is capable to clear Aβ fibrils. Moreover, compound dose-dependently decreases β-site amyloid precursor protein cleaving enzyme (1BACE-1) activity with EC value in micromolar range. Thus our study has revealed that CID 9998128 is a good candidate for AD treatment through preventing production of Aβ peptides and degrading their...
International Journal of Biological Macromolecules, 2015
We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the the... more We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the thermal stability and fibrillation of human insulin. Thermostability of human insulin used differential scanning calorimetry (DSC), which showed two phase-transitions for insulin at 60 and 82°C. After adding dendrimers at 0.6μmol/l, the first peaks disappeared and the second peaks were higher. We posited that, in the presence of dendrimers, the dimers in the solution were transformed into hexamers. The effect of dendrimers on insulin fibrillation was monitored by measuring ThT fluorescence, and visualization of insulin fibrils by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The effect of PAMAM dendrimers on insulin fibrillation was strongly dependent on the dendrimers generation and dendrimer:protein ratio.
It is well known that misfolded peptides/proteins can play a role in processes of normal ageing a... more It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer's disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer's disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer's disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer's disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer's ...
Cytochrome c oxidase binds protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) with high... more Cytochrome c oxidase binds protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) with high affinity. There are 1.46 high-affinity binding sites per cytochrome c oxidase for CCCP with dissociation constant 2.7 x 10(-7) mol/l. The bond between the CCCP and cytochrome c oxidase accomplishes through the group on cytochrome c oxidase with pKa 6.64 and is based on the electrostatic interaction. Interaction of CCCP with low-affinity binding sites of cytochrome c oxidase induces the shift of the anion CCCP spectrum to UV-region. The similar effect is characteristic for CCCP interaction with protons. Lipophilic non-dissociated derivative NCH3CCP is not binding to cytochrome c oxidase.
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Papers by Zuzana Gazova