| 1. |
- Awadalla, M. K. A., et al.
(författare)
-
Improved Homology Model of the Human all-trans Retinoic Acid Metabolizing Enzyme CYP26A1
- 2016
-
Ingår i: Molecules. - : MDPI AG. - 1420-3049 .- 1431-5157. ; 21:3
-
Tidskriftsartikel (refereegranskat)abstract
- A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).
|
|
| 2. |
- Bermúdez, Eduardo, et al.
(författare)
-
Improved homology model of cyclohexanone monooxygenase from Acinetobacter calcoaceticus based on multiple templates
- 2014
-
Ingår i: Computational biology and chemistry. - : Elsevier BV. - 1476-9271 .- 1476-928X. ; 49, s. 14-22
-
Tidskriftsartikel (refereegranskat)abstract
- A new homology model of cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus is derived based on multiple templates, and in particular the crystal structure of CHMO from Rhodococcus sp. The derived model was fully evaluated, showing that the quality of the new structure was improved over previous models. Critically, the nicotinamide cofactor is included in the model for the first time. Analysis of several molecular dynamics snapshots of intermediates in the enzymatic mechanism led to a description of key residues for cofactor binding and intermediate stabilization during the reaction, in particular Arg327 and the well known conserved motif (FxGxxxHxxxW) in Baeyer-Villiger monooxygenases, in excellent agreement with known experimental and computational data. © 2014 Elsevier Ltd.
|
|
| 3. |
- Bermúdez, Eduardo, et al.
(författare)
-
Mechanism of the organocatalyzed decarboxylative Knoevenagel-Doebner reaction. A theoretical study.
- 2010
-
Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 114:50, s. 13086-92
-
Tidskriftsartikel (refereegranskat)abstract
- We have investigated important intermediates and key transition states of the organocatalyzed Knoevenagel condensation using density functional theory and two different basis sets (6-31 G(d,p) and 6-311++G(2df,2pd)), both in gas phase and simulating the bulk solvent (pyridine) using the PCM method. Calculated structures for reactants, intermediates, and key transition states suggest that the secondary amine catalyst is essential, both for activating the aldehyde for nucleophilic attack, and in the possible decarboxylation pathways. The calculated results are shown to agree with available experimental information. On the basis of the results obtained, the studied mechanism may be important in the understanding of vinylphenol production during malting and brewing of wheat and barley grains.
|
|
| 4. |
- Billod, Jean-Marc, et al.
(författare)
-
Structures, Properties, and Dynamics of Intermediates in eEF2-Diphthamide Biosynthesis
- 2016
-
Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 56:9, s. 1776-1786
-
Tidskriftsartikel (refereegranskat)abstract
- The eukaryotic translation Elongation Factor 2 (eEF2) is an essential enzyme in protein synthesis. eEF2 contains a unique modification of a histidine (His699 in yeast; HIS) into diphthamide (DTA), obtained via 3-amino-3-carboxypropyl (ACP) and diphthine (DTI) intermediates in the biosynthetic pathway. This essential and unique modification is also vulnerable, in that it can be efficiently targeted by NAD(+)-dependent ADP-ribosylase toxins, such as diphtheria toxin (DT). However, none of the intermediates in the biosynthesis path is equally vulnerable against the toxins. This study aims to address the different susceptibility of DTA and its precursors against bacterial toxins. We have herein undertaken a detailed in silico study of the structural features and dynamic motion of different His699 intermediates along the diphthamide synthesis pathway (HIS, ACP, DTI, DTA). The study points out that DTA forms a strong hydrogen bond with an asparagine which might explain the ADP-ribosylation mechanism caused by the diphtheria toxin (DT). Finally, in silico mutagenesis studies were performed on the DTA modified protein, in order to hamper the formation of such a hydrogen bond. The results indicate that the mutant structure might in fact be less susceptible to attack by DT and thereby behave similarly to DTI in this respect.
|
|
| 5. |
- Biundo, Antonino, et al.
(författare)
-
Enzyme Modification
- 2021
-
Ingår i: Biocatalysis for Practitioners. - : Wiley. ; , s. 33-62
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The chapter on protein engineering has introduced and discussed an overview of the available methods for the modification of enzymes. Starting with the classical directed evolution (DE) technique, which has been applied extensively throughout several different biocatalytic processes, the reader moves toward the semi-rational, rational, and de novo design of enzymes. Meanwhile, DE is clearly the current industry-leading technology; depending on the understanding of the particular enzymatic system, and on the available structural information, other techniques such as rational design are also becoming fast and efficient solutions for the development of new catalysts. This success would not be possible without the constant improvements of the computational techniques and the newly developed modeling systems for enzyme engineering.
|
|
| 6. |
- Bottinelli, F., et al.
(författare)
-
Computational study of the initial step in the mechanism of dehaloperoxidase A : Determination of the protonation scheme at the active site and the movement of the His55 residue
- 2015
-
Ingår i: Quantum Modeling of Complex Molecular Systems. - Cham : Springer. ; , s. 367-382
-
Bokkapitel (refereegranskat)abstract
- Dehalopeoxidase A (DHP A) is a detoxifying enzyme found in the marine worm Amphitrite ornata. This enzyme converts halophenols found in the environment where the worm lives, into quinones by dehalogenation. The enzyme has globin structure and function, but works also as a peroxidase in the presence of H2O2 which binds to the iron present in the heme group. The initial step in the enzymatic reaction path is the transformation of the heme Fe(III) ion into a ferryl (Fe = O) moiety. A distal histidine, His55, is crucial for this process. His55 can occupy two positions, either in the distal pocket of the active center (“closed”), or exposed to the solvent (“open”). NMR experiments show that His55 moves between those positions in the resting state of the enzyme. For this process to occur it is necessary that a gate, composed of a triad Asn37-Lys36-Lys51 and two carboxylates on the heme group, suffer a conformational change before and after the passage of the histidine. We examined computationally this process at the B3LYP/6-31G(d,p) level, within a PCM simulated aqueous environment. This analysis leads us to propose a correction of the experimental structure of the enzyme determined by X-ray crystallography and offers an explanation for different conformations of the twin carboxylates at the heme group observed in the crystals. This new proposal agrees with the experimentally determined electron density distributions and explains the role of the His55 as a functional hook for the peroxide in the aqueous media.
|
|
| 7. |
- Brovetto, Margarita, et al.
(författare)
-
C-C Bond-Forming Lyases in Organic Synthesis
- 2011
-
Ingår i: Chemical Reviews. - : American Chemical Society (ACS). - 0009-2665 .- 1520-6890. ; 111:7, s. 4346-4403
-
Forskningsöversikt (refereegranskat)
|
|
| 8. |
- Cerecetto, Hugo, et al.
(författare)
-
1, 2, 4-Triazine N-oxide derivatives : studies as potential hypoxic cytotoxins. Part III.
- 2004
-
Ingår i: Archiv der Pharmazie. - : Wiley. - 0365-6233 .- 1521-4184. ; 337:5, s. 271-80
-
Tidskriftsartikel (refereegranskat)abstract
- New 5-(2-arylethenyl)-1, 2, 4-triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than Tirapazamine, 3-aminobenzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective. Some derivatives were studied as DNA-binding agents in oxic conditions showing poor affinity for this biomolecule. This result showed that the cytotoxic activity in oxia is DNA damage not dependent. Electrochemical and ESR spectroscopy studies were performed in order to determine the ability of compounds to produce radicals and the relation of these in the mechanism of cytotoxicity.
|
|
| 9. |
- Cerecetto, Hugo, et al.
(författare)
-
1, 2, 4-Triazine N-oxide derivatives : studies as potential hypoxic cytotoxins. Part II.
- 2004
-
Ingår i: Archiv der Pharmazie. - : Weinheim Verlag. - 0365-6233 .- 1521-4184. ; 337:5, s. 247-258
-
Tidskriftsartikel (refereegranskat)abstract
- New 1, 2, 4-Triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The starting heterocycles have been prepared using a standard microwave oven in a clean and good-yielded process. The reactivity of methyl-1, 2, 4-triazine N(4)-oxide and N(1), N(4)-dioxide with different electrophilic agents has been studied. The desired products were obtained only when iminium electrophiles were employed. The regioselectivity of this process has been studied by means of experimental and theoretical (at ab initio level) procedures. Theoretically was expected that the most stable intermediates where the benzylic-like anion from position 5. A fact which agreed with the experimental observed regioselectivity. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than tirapazamine, 3-amino-benzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 19, 6-methyl-5-[2-(5-nitrothienyl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective.
|
|
| 10. |
- Cerecetto, H, et al.
(författare)
-
1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs : structure-activity relationships.
- 1999
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 42:11, s. 1941-50
-
Tidskriftsartikel (refereegranskat)abstract
- The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.
|
|
