| 1. |
- Cerezo, J., et al.
(författare)
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Antioxidant properties of beta-carotene isomers and their role in photosystems: insights from ab initio simulations
- 2012
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Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 116:13, s. 3498-3506
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Tidskriftsartikel (refereegranskat)abstract
- In this work we investigate the effect of cis isomerizations and conformational changes on the antioxidant activity of β-carotene, one of the most important pigments in nature. The electrodonating (ω−) and electroaccepting (ω+) powers of the most relevant isomers of β-carotene are first evaluated in polar and nonpolar solvents using density functional theory (DFT), and these quantities are then used to establish an antioxidant scale of the isomers. The electrodonating power, which is directly related to the antioxidant activity, is shown to provide a very good correlation with the experimental data. Next, we compute the intermediate twisted structures of the β-carotene isomers generated by partial rotation of every single bond in the polyenic chain. The electrodonating and electroaccepting powers are evaluated for each of these intermediate structures along with their maximum absorption wavelengths, which are computed using time-dependent DFT (TD-DFT). The trends observed for both the electrodonating power and the maximum absorption wavelength can be rationalized in terms of the effective conjugated chain length of the structure resulting from single bond rotations. The results obtained are used to analyze the conformational distribution of β-carotene in the well-resolved photosystem I (PS-I) of purple cyanobacteria. It is then shown that the isomers present in this photosystem are those having the lowest calculated relative energies and that those with enhanced antioxidant activity are preferentially located in the inner core of the protein complex.
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| 2. |
- Gao, Chunxia, et al.
(författare)
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Rational design and validation of a Tip60 histone acetyltransferase inhibitor
- 2014
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.
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| 3. |
- Patridge, Erik V., et al.
(författare)
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7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide
- 2012
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 86:10, s. 1613-1625
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Tidskriftsartikel (refereegranskat)abstract
- Here, we report on 7-nitro-4-(phenylthio)benzofurazan (NBF-SPh), the most potent derivative among a set of patented anticancer 7-nitrobenzofurazans (NBFs), which have been suggested to function by perturbing protein-protein interactions. We demonstrate that NBF-SPh participates in toxic redox-cycling, rapidly generating reactive oxygen species (ROS) in the presence of molecular oxygen, and this is the first report to detail ROS production for any of the anticancer NBFs. Oxygraph studies showed that NBF-SPh consumes molecular oxygen at a substantial rate, rivaling even plumbagin, menadione, and juglone. Biochemical and enzymatic assays identified superoxide and hydrogen peroxide as products of its redox-cycling activity, and the rapid rate of ROS production appears to be sufficient to account for some of the toxicity of NBF-SPh (LC50 = 12.1 mu M), possibly explaining why tumor cells exhibit a sharp threshold for tolerating the compound. In cell cultures, lipid peroxidation was enhanced after treatment with NBF-SPh, as measured by 2-thiobarbituric acid-reactive substances, indicating a significant accumulation of ROS. Thioglycerol rescued cell death and increased survival by 15-fold to 20-fold, but pyruvate and uric acid were ineffective protectants. We also observed that the redox-cycling activity of NBF-SPh became exhausted after an average of approximately 19 cycles per NBF-SPh molecule. Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity.
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| 4. |
- Czegeny, G., et al.
(författare)
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Hydrogen peroxide contributes to the ultraviolet-B (280-315 nm) induced oxidative stress of plant leaves through multiple pathways
- 2014
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Ingår i: Febs Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 588:14, s. 2255-2261
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Tidskriftsartikel (refereegranskat)abstract
- Solar UV-B (280-315 nm) radiation is a developmental signal in plants but may also cause oxidative stress when combined with other environmental factors. Using computer modeling and in solution experiments we show that UV-B is capable of photosensitizing hydroxyl radical production from hydrogen peroxide. We present evidence that the oxidative effect of UV-B in leaves is at least twofold: (i) it increases cellular hydrogen peroxide concentrations, to a larger extent in pyridoxine antioxidant mutant pdx1.3-1 Arabidopsis and; (ii) is capable of a partial photo-conversion of both 'natural' and 'extra' hydrogen peroxide to hydroxyl radicals. As stress conditions other than UV can increase cellular hydrogen peroxide levels, synergistic deleterious effects of various stresses may be expected already under ambient solar UV-B. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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| 5. |
- Eizaguirre, A., et al.
(författare)
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Stability and iron coordination in DNA adducts of Anthracycline based anti-cancer drugs
- 2012
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 14:36, s. 12505-12514
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Tidskriftsartikel (refereegranskat)abstract
- There is evidence that the interaction of the alpha-ketol group of the Doxorubicin and Epirubicin anti-cancer drugs with Fe(III) generates hydroxyl radicals under aerobic conditions, causing cardiotoxicity in patients. Considering that the formation of DNA adducts is one of the main targets of Anthracycline drugs, we have in the present study characterized several [Anthracycline-DNA]Fe(III) complexes with respect to their stability and Fe(III) coordination, by means of MD simulations. Iron is found to coordinate well to the drugs containing an alpha-ketol group, this being the only group of the drug that binds to the metal. The complexes containing an alpha-ketol group, [Doxorubicin-DNA]Fe(III) and [Epirubicin-DNA]Fe(III), thus show greater stability than those not containing it, i.e., [Daunorubicin-DNA]Fe(III), [Idarubicin-DNA]Fe(III) and [5-Imino-Daunorubicin]Fe(III). Metal attachment to the alpha-ketol group is furthermore facilitated by the phosphate groups of DNA. The coordination to iron in the [Doxorubicin-DNA]Fe(III) system is smaller than that found for the [Epirubicin-DNA]Fe(III) system, and the corresponding number of coordinating waters in the former is larger than in the latter. This may in turn result in higher hydroxyl radical production, thus explaining the increased cardiotoxicity noted for Doxorubicin.
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| 6. |
- Eriksson, Emma S. E., et al.
(författare)
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De novo tertiary structure prediction using RNA123-benchmarking and application to Macugen
- 2014
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 20:8
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Tidskriftsartikel (refereegranskat)abstract
- The present benchmarking study utilizes the RNA123 program for de novo prediction of tertiary structures of a set of 50 RNA molecules for which X-ray/NMR structures are available, based on the nucleic acid sequence only. All molecules contain a hairpin loop motif and a helical structure of canonical and non-canonical base pairs, interrupted by bulges and internal loops to various degrees. RNA molecules with double helices made up purely by canonical base pairing, and molecules containing symmetric internal loops of non-canonical base pairing are, overall, very well predicted. Structures containing bulges and asymmetric internal loops, and more complex structures containing multiple bulges and internal loops in the same molecule, result in larger deviations from their X-ray/NMR predicted structures due to higher degree of flexibility of the nucleotide bases in these regions. In a majority of the molecules included herein, the RNA123 program was, however, able to predict the tertiary structure with a heavy atom RMSD of less than 5 angstrom to the X-ray/NMR structure, and the models were in most cases structurally closer to the X-ray/NMR structures than models predicted by MC-Fold and MC-Sym. A set of RNA molecules containing pseudoknot tertiary structure motifs were included, but neither of the programs was able to predict the folding of the single-stranded stem onto the helix without additional structural input. The RNA123 program was then applied to predict the tertiary structure of the RNA segment of Macugen (R), the first RNA aptamer approved for clinical use, and for which no tertiary structure has yet been solved. Four possible tertiary structures were predicted for this 27-nucleic-acid-long RNA molecule, which will be used in constructing a full model of the PEGylated aptamer and its interaction with the vascular endothelial growth factor target.
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| 7. |
- Eriksson, Emma S. E., et al.
(författare)
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Identifying the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) as a potential target for hypericin - a theoretical study
- 2012
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 14:36, s. 12637-12646
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Tidskriftsartikel (refereegranskat)abstract
- The exact cellular target for the potent anti-cancer agent hypericin has not yet been determined; this thus encourages the application of computational chemistry tools to be employed in order to provide insights that can be employed in further drug development studies. In the present study computational docking and molecular dynamics simulations are applied to investigate possible interactions between hypericin and the Ca2+ pump SERCA as proposed in the literature. Hypericin was found to bind strongly both in pockets within the transmembrane region and in the cytosolic region of the protein, although the two studied isoforms of SERCA differ slightly in their preferred binding sites. The calculated binding energies for hypericin in the four investigated sites were of the same magnitude as for thapsigargin (TG), the most potent SERCA inhibitor, or in the range between TG and di-tert-butylhydroquinone (BHQ), which is also known to possess inhibitory activity. The hydrophobic character of hypericin indicates that the molecule initially binds in the ER membrane from which it diffuses into the transmembrane region of the protein and to binding pockets therein. The transmembrane TG and BHQ binding pockets provide suitable locations for hypericin as they allow for favourable interactions with the lipid tails that surround these. High binding energies were noted for hypericin in these pockets and are expected to constitute highly possible binding sites due to their accessibility from the ER membrane. Hypericin most likely binds to both isoforms of SERCA and acts as an inhibitor or, under light irradiation, as a singlet oxygen generator that in turn degrades the protein or induces lipid peroxidation.
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| 8. |
- Grand, A., et al.
(författare)
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Comparison of the Mechanism of Deamination of 5,6-dihydro-5-methylcytosine with other cytosine derivatives
- 2012
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 131:4
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of deamination of 5,6-dihydro-5-methylcytosine has been investigated theoretically and compared to those of other cytosine derivatives. The main goal is to understand the effect of C5-methylation and C5–C6 saturation upon the deamination rate. It is found that C5–C6 saturation tends to increase the local electrophilicity of the cytosine derivative on carbon C4. It is also concluded that C5-methylation displays an opposite effect on saturated versus unsaturated systems: on unsaturated systems, C5-methylation tends to increase the local electrophilicity on C4, while it reduces the local electrophilicity on C4 for saturated ones.
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| 9. |
- Grand, A., et al.
(författare)
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Deamination features of 5-hydroxymethylcytosine, a radical and enzymatic DNA oxidation product
- 2014
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 20:6
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Tidskriftsartikel (refereegranskat)abstract
- The 5-methylcytosine derivative 5-hydroxymethylcytosine (5hmCyt), which is generated via enzymatic oxidation, is sometimes referred to as the sixth nucleobase due to its widespread presence in the DNA of brain and embryonic stem cells. In this study, we used density functional based methods and reactivity indices from conceptual DFT to explore the mechanism and key features of the hydrolytic deamination of 5hmCyt. The data obtained are used to compare and contrast this deamination reaction with those of other cytosine derivatives. The deamination process for 5hmCyt is similar to the corresponding processes for other unsaturated derivatives in that the amino form is the reactive one and water addition is the rate-limiting step. However, several differences due to the rotameric asymmetry of the current system are also noted.
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| 10. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs : Development, Validation, and Simulations with a Coarse-Grained Model
- 2014
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:1, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are proposed as drug delivery systems and can in principle be designed so as to cohere with specific tissue types or local environments. However, little detail is known about the exact mechanisms for drug delivery and the distributions of drug molecules inside the lipid carrier. In the current work, a coarse-grained (CG) liposome model is developed, consisting of over 2500 lipids, with varying degrees of drug loading. For the drug molecule, we chose hypericin, a natural compound proposed for use in photodynamic therapy, for which a CG model was derived and benchmarked against corresponding atomistic membrane bilayer model simulations. Liposomes with 21-84 hypericin molecules were generated and subjected to 10 microsecond simulations. Distribution of the hypericins, their orientations within the lipid bilayer, and the potential of mean force for transferring a hypericin molecule from the interior aqueous droplet through the liposome bilayer are reported herein.
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