| 1. |
- Napolitano, C., et al.
(författare)
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Synthesis, kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 68:27-28, s. 5533-5540
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Tidskriftsartikel (refereegranskat)abstract
- Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin. (c) 2012 Elsevier Ltd. All rights reserved.
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| 2. |
- Eriksson, Leif A., 1964-, et al.
(författare)
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Tetrazole derivatives as cytochrome p450 inhibitors
- 2019
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Patent (populärvet., debatt m.m.)abstract
- According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
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| 3. |
- Saenz Mendez, Patricia, et al.
(författare)
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Homology models of human all-trans retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced-variant.
- 2012
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Ingår i: Journal of Chemical Information and Modeling. - Washington, USA : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 52:10, s. 2631-2637
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Tidskriftsartikel (refereegranskat)abstract
- Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.
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| 4. |
- Wu, Min, 1986, et al.
(författare)
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Theoretical study of pyridoxine (vitamin b6) photolysis.
- 2011
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Ingår i: The journal of physical chemistry. A. - : American Chemical Society (ACS). - 1520-5215 .- 1089-5639. ; 115:46, s. 13556-63
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Tidskriftsartikel (refereegranskat)abstract
- Two different reaction types for the photolysis of pyridoxine-aromatic ring-opening and photodissociation-have been studied in the Density Functional Theory (DFT) framework. Our results show that neither photolytic ring-opening, dehydroxymethylation, demethylation nor dehydroxylation from the aromatic ring can be induced spontaneously in UV-irradiated pyridoxine, due to the high barriers along the reaction coordinates in the excited states. However, the simultaneous dehydroxylation of the C4-bound hydroxymethyl group and dehydrogenation of the ring bound hydroxyl substituent, selectively generating ortho-quinone methide and water, does occur after UV exposure. The findings correlate very well with available experimental data. The geometries of pyridoxine, its various transition states and products are optimized in the ground and first excited states in vacuum within the TD-DFT formalism.
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| 5. |
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| 6. |
- Bushnell, Eric A. C., et al.
(författare)
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The first branching point in porphyrin biosynthesis : a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
- 2011
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Ingår i: Journal of Computational Chemistry. - New York : John Wiley & Sons. - 0192-8651 .- 1096-987X. ; 32:5, s. 822-834
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Tidskriftsartikel (refereegranskat)abstract
- In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.
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| 7. |
- Erdtman, Edvin, 1981-
(författare)
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5-Aminolevulinic acid and derivatives thereof : properties, lipid permeability and enzymatic reactions
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.
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| 8. |
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| 9. |
- Erdtman, Edvin, et al.
(författare)
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Computational studies on Schiff-base formation : Implications for the catalytic mechanism of porphobilinogen synthase
- 2011
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Ingår i: Computational and Theoretical Chemistry. - Amsterdam : Elsevier. - 2210-271X .- 2210-2728. ; 963:2-3, s. 479-489
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Tidskriftsartikel (refereegranskat)abstract
- Schiff bases are common and important intermediates in many bioenzymatic systems. The mechanism by which they are formed, however,is dependent on the solvent, pH and other factors. In the present study we have used density functional theory methods in combination with appropriate chemical models to get a better understanding of the inherent chemistry of the formation of two Schiff bases that have been proposed to be involved in the catalytic mechanism of porphobilinogensynthase (PBGS), a key enzyme in the biosynthesis of porphyrins. More specifically, we have investigated the uncatalysed reaction of its substrate 5-aminolevulinic acid (5-ALA) with a lysine residue for theformation of the P-site Schiff base, and as possibly catalysed by the second active site lysine, water or the 5-ALA itself. It is found that cooperatively both the second lysine and the amino group of the initial 5-ALA itself are capable of reducing the rate-limiting energy barrier to14.0 kcal mol-1. We therefore propose these to be likely routes involved in the P-site Schiff-base formation in PBGS.
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| 10. |
- Erdtman, Edvin, et al.
(författare)
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Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
- 2008
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Ingår i: Chemical Physics Letters. - Amsterdam : North-Holland Publishing Co. - 0009-2614 .- 1873-4448. ; 463:1-3, s. 178-182
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Tidskriftsartikel (refereegranskat)abstract
- 5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.
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