oru.sePublikationer
Ändra sökning
Avgränsa sökresultatet
1 - 28 av 28
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1.
    Bushnell, Eric A C
    et al.
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Erdtman, Edvin
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Llano, Jorge
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Eriksson, Leif A.
    National University of Ireland, Galway, University Road, Galway, Ireland.
    Gauld, James W.
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III DecarboxylaseManuskript (preprint) (Övrigt vetenskapligt)
  • 2.
    Bushnell, Eric A. C.
    et al.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Erdtman, Edvin
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Llano, Jorge
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    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 decarboxylase2011Ingår i: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, nr 5, s. 822-834Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 3.
    Erdtman, Edvin
    Örebro universitet, Akademin för naturvetenskap och teknik.
    5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    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.

    Delarbeten
    1. Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
    Öppna denna publikation i ny flik eller fönster >>Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
    2007 (Engelska)Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, nr 1-3, s. 101-106Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

    Ort, förlag, år, upplaga, sidor
    Amsterdam: North-Holland Publishing Co, 2007
    Nyckelord
    5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
    Nationell ämneskategori
    Teoretisk kemi Fysikalisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
    Tillgänglig från: 2007-06-25 Skapad: 2007-06-25 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    2. Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
    Öppna denna publikation i ny flik eller fönster >>Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
    2008 (Engelska)Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, nr 18, s. 4367-4374Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

    Ort, förlag, år, upplaga, sidor
    Washington DC: American Chemical Society, 2008
    Nyckelord
    Aminolevulinic Acid/*chemistry, Carboxylic Acids/chemistry, Catalysis, Isomerism, Protons, Quantum Theory, Thermodynamics, Water/chemistry
    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    3. Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
    Öppna denna publikation i ny flik eller fönster >>Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
    2008 (Engelska)Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, nr 1-3, s. 178-182Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    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.

    Ort, förlag, år, upplaga, sidor
    Amsterdam: North-Holland Publishing Co, 2008
    Nyckelord
    Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Läkemedelskemi Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    4. Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen Synthase
    Öppna denna publikation i ny flik eller fönster >>Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen Synthase
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Teoretisk kemi Fysikalisk kemi
    Forskningsämne
    Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-9948 (URN)
    Tillgänglig från: 2010-03-12 Skapad: 2010-03-10 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    5. Modelling the mechanism of porphobilinogen synthase
    Öppna denna publikation i ny flik eller fönster >>Modelling the mechanism of porphobilinogen synthase
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Fysikalisk kemi; Biokemi
    Identifikatorer
    urn:nbn:se:oru:diva-9949 (URN)
    Tillgänglig från: 2010-03-12 Skapad: 2010-03-10 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    6. Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III Decarboxylase
    Öppna denna publikation i ny flik eller fönster >>Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III Decarboxylase
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Fysikalisk kemi; Biokemi
    Identifikatorer
    urn:nbn:se:oru:diva-9950 (URN)
    Tillgänglig från: 2010-03-12 Skapad: 2010-03-10 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
  • 4.
    Erdtman, Edvin
    Örebro universitet, Institutionen för naturvetenskap.
    A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability2008Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    5-aminolevulinic acid (5ALA) is a widely used prodrug in Photodynamic therapy (PDT). The target molecule in 5ALA-PDT is Protoporphyrin IX (PpIX), which is synthesized endogenously via the heme pathway in the cell. In this thesis; the structural and energetic properties of 5ALA, its methyl-, ethyl- and hexyl esters, four different 5ALA enols, and hydrated 5ALA have been investigated using Quantum Mechanical (QM) first principles calculations. The vacuum proton affinity (PA) of 5ALA is found to be in good agreement with other similar compounds. The keto-enol tautomerization mechanism of 5ALA has been studied, and a self-catalysis mechanism has been proposed to be the most probable. Molecular Dynamics (MD) simulations of a lipid bilayer have been performed to study the membrane permeability of 5ALA and its esters. In the simulations the molecules were inserted in the middle of the membrane, equilibrated, and then simulated in 20 ns. It has been found that there are some differences in penetration between the molecules studied. The methyl ester of 5ALA is diverging from the others by having its barrier not in the middle of the membrane, as the others have.

    Delarbeten
    1. Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
    Öppna denna publikation i ny flik eller fönster >>Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
    2007 (Engelska)Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, nr 1-3, s. 101-106Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

    Ort, förlag, år, upplaga, sidor
    Amsterdam: North-Holland Publishing Co, 2007
    Nyckelord
    5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
    Nationell ämneskategori
    Teoretisk kemi Fysikalisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
    Tillgänglig från: 2007-06-25 Skapad: 2007-06-25 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    2. Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
    Öppna denna publikation i ny flik eller fönster >>Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
    2008 (Engelska)Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, nr 18, s. 4367-4374Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

    Ort, förlag, år, upplaga, sidor
    Washington DC: American Chemical Society, 2008
    Nyckelord
    Aminolevulinic Acid/*chemistry, Carboxylic Acids/chemistry, Catalysis, Isomerism, Protons, Quantum Theory, Thermodynamics, Water/chemistry
    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
    3. Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
    Öppna denna publikation i ny flik eller fönster >>Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
    2008 (Engelska)Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, nr 1-3, s. 178-182Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    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.

    Ort, förlag, år, upplaga, sidor
    Amsterdam: North-Holland Publishing Co, 2008
    Nyckelord
    Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Läkemedelskemi Fysikalisk kemi Teoretisk kemi
    Forskningsämne
    Biokemi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2019-12-13Bibliografiskt granskad
  • 5.
    Erdtman, Edvin
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Bushnell, Eric A. C.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    School of Chemistry, National University Ireland (NUI) Galway, Galway, Ireland.
    Computational insights into the mechanism of porphobilinogen synthase2010Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, nr 50, s. 16860-16870Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Porphobilinogen synthase (PBGS) is a key enzyme in heme biosynthesis that catalyzes the formation of porphobilinogen (PBG) from two 5-aminolevulinic acid (5-ALA) molecules via formation of intersubstrateC-N and C-C bonds. The active site consists of several invariant residues, including two lysyl residues (Lys210 and Lys263; yeast numbering) that bind the two substrate moieties as Schiff bases. Based on experimental studies, various reaction mechanisms have been proposed for this enzyme that generally can be classified according to whether the intersubstrate C-C or C-N bond is formed first. However, the detailed catalytic mechanism of PBGS remains unclear. In the present study, we have employed density functional theory methods in combination with chemical models of the two key lysyl residues and two substrate moieties in order to investigate various proposed reaction steps and gain insight into the mechanism of PBGS. Importantly, it is found that mechanisms in which the intersubstrate C-N bond is formed first have a ratelimiting barrier (17.5 kcal/mol) that is lower than those in which the intersubstrate C-C bond is formed first (22.8 kcal/mol).

  • 6.
    Erdtman, Edvin
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Bushnell, Eric A. C.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    School of Chemistry, National University of Ireland (NUI Galway), Galway, Ireland.
    Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase2011Ingår i: Computational and Theoretical Chemistry, ISSN 2210-271X, E-ISSN 2210-2728, Vol. 963, nr 2-3, s. 479-489Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 7.
    Erdtman, Edvin
    et al.
    Örebro universitet, Institutionen för naturvetenskap.
    dos Santos, Daniel J. V. A.
    Löfgren, Lennart
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer2008Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, nr 1-3, s. 178-182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 8.
    Erdtman, Edvin
    et al.
    Örebro universitet, Institutionen för naturvetenskap.
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives2007Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, nr 1-3, s. 101-106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

  • 9.
    Erdtman, Edvin
    et al.
    Örebro universitet, Institutionen för naturvetenskap.
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism2008Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, nr 18, s. 4367-4374Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

  • 10.
    Erdtman, Edvin
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Gauld, James W
    Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B.
    Eriksson, Leif A.
    School of Chemistry, NUI Galway, Galway, Ireland.
    Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen SynthaseManuskript (preprint) (Övrigt vetenskapligt)
  • 11.
    Erdtman, Edvin
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B.
    Eriksson, Leif A.
    School of Chemistry, NUI Galway, Galway, Ireland.
    Modelling the mechanism of porphobilinogen synthaseManuskript (preprint) (Övrigt vetenskapligt)
  • 12.
    Eriksson, Leif A.
    et al.
    Göteborgs universitet, Göteborg.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Tetrazole derivatives as cytochrome p450 inhibitors2019Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    According to the invention there is provided a compound of formula I, wherein Rand Rhave meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.

  • 13.
    Huang, Shuo
    et al.
    Applied Materials Physics, Department of Materials Science and Engineering, Royal Institute of Technology, Stockholm, Sweden.
    Holmstrom, Erik
    Sandvik Coromant R&D, Stockholm, Sweden.
    Eriksson, Olle
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Physics and Astronomy, Division of Materials Theory, Uppsala University, Uppsala, Sweden.
    Vitos, Levente
    Applied Materials Physics, Department of Materials Science and Engineering, Royal Institute of Technology, Stockholm, Sweden; Department of Physics and Astronomy, Division of Materials Theory, Uppsala University, Uppsala, Sweden; Institute for Solid State Physics and Optics, Wigner Research Centre for Physics, Budapest, Hungary.
    Mapping the magnetic transition temperatures for medium- and high-entropy alloys2018Ingår i: Intermetallics (Barking), ISSN 0966-9795, E-ISSN 1879-0216, Vol. 95, s. 80-84Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tailorable magnetic state near room temperature is very promising for several technological, including magnetocaloric applications. Here using first-principle alloy theory, we determine the Curie temperature (T-C) of a number of equiatomic medium- and high-entropy alloys with solid solution phases. All calculations are performed at the computed lattice parameters, which are in line with the available experimental data. Theory predicts a large crystal structure dependence of T-C, which explains the experimental observations under specified conditions. The sensitivity of the magnetic state to the crystal lattice is reflected by the magnetic exchange interactions entering the Heisenberg Hamiltonian. The analysis of the effect of composition on T-C allows researchers to explore chemistry-dependent trends and design new multi-component alloys with pre-assigned magnetic properties.

  • 14.
    Koivuniemi, Artturi
    et al.
    VTT Bio- and Chemical Processes, Espoo, Finland.
    Sysi-Aho, Marko
    VTT Bio- and Chemical Processes, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Bio- and Chemical Processes, Espoo, Finland.
    Ollila, Samuli
    Physical Chemistry, Lund University, Lund, Sweden.
    Interfacial properties of high-density lipoprotein-like lipid droplets with different lipid and apolipoprotein A-I compositions2013Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, nr 10, s. 2193-2201, artikel-id S0006-3495(13)00366-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The surface properties of high-density lipoproteins (HDLs) are important because different enzymes bind and carry out their functions at the surface of HDL particles during metabolic processes. However, the surface properties of HDL and other lipoproteins are poorly known because they cannot be directly measured for nanoscale particles with contemporary experimental methods. In this work, we carried out coarse-grained molecular dynamics simulations to study the concentration of core lipids in the surface monolayer and the interfacial tension of droplets resembling HDL particles. We simulated lipid droplets composed of different amounts of phospholipids, cholesterol esters (CEs), triglycerides (TGs), and apolipoprotein A-Is. Our results reveal that the amount of TGs in the vicinity of water molecules in the phospholipid monolayer is 25-50% higher compared to the amount of CEs in a lipid droplet with a mixed core of an equal amount of TG and CE. In addition, the correlation time for the exchange of molecules between the core and the monolayer is significantly longer for TGs compared to CEs. This suggests that the chemical potential of TG is lower in the vicinity of aqueous phase but the free-energy barrier for the translocation between the monolayer and the core is higher compared to CEs. From the point of view of enzymatic modification, this indicates that TG molecules are more accessible from the aqueous phase. Further, our results point out that CE molecules decrease the interfacial tension of HDL-like lipid droplets whereas TG keeps it constant while the amount of phospholipids varies.

  • 15. Li, Xin
    et al.
    Rinkevicius, Zilvinas
    Tu, Yaoquan
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Tian, He
    Ågren, Hans
    Paramagnetic Perturbation of the 19F NMR Chemical Shift in Fluorinated Cysteine by O2: A Theoretical Study2009Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, nr 31, s. 10916-10922Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present a combined molecular dynamics and density functional theory study of dioxygen-induced perturbation of the 19F NMR chemical shifts in an aqueous solution of fluorinated cysteine under 100 atm of O2 partial pressure. Molecular dynamics simulations are carried out to determine the dominant structures of O2 and the fluorinated cysteine complexes in water, and the collected structural information is exploited in computation of 19F chemical shifts using density functional theory. The obtained results indicate that the density redistribution of the O2 unpaired electrons between the dioxygen and fluorinated cysteine is responsible for the experimentally observed perturbation of the 19F NMR chemical shifts, where the Fermi contact interaction plays the key role. The O2-induced paramagnetic 19F chemical shift, averaged over the simulation trajectory, is comparable with the reported experimental values, proving the availability of the developed strategy for modeling 19F NMR chemical shifts in the presence of paramagnetic agents in an aqueous solution. The applicability of the combined molecular dynamics/density functional theory approach for dioxygen NMR perturbation to all resonating nuclei including 1H, 13C, 15N, and 19F is emphasized, and the ramification of this for investigations of membrane protein structures is discussed.

  • 16.
    Musa, Klefah A. K.
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Eriksson, Leif A.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Photophysical and photochemical properties and photodehalogenation of antibiotic drug lomefloxacinManuskript (preprint) (Övrigt vetenskapligt)
  • 17.
    Musa, Klefah A. K.
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Palawi, Viraja R.
    Eriksson, Leif A.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    New non-steroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivityManuskript (preprint) (Övrigt vetenskapligt)
  • 18.
    Musa, Klefah A. K.
    et al.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Palwai, Viraja R.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Eriksson, Leif A.
    Örebro universitet, Akademin för naturvetenskap och teknik.
    New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity2011Ingår i: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 111, nr 6, s. 1184-1195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic, analgesic, and anti-inflammatory agents. However, they are also associated with a range of side effects, from phototoxicity due to excited state induced decarboxylation to severe conditions in the gastrointestinal tract caused by inhibition of the COX-1 isoform of the target cyclooxygenase enzyme. In the current work, new derivatives of the three NSAIDs ketoprofen, ibuprofen, and naproxen were designed. Their photochemistry was explored using hybrid-density functional theory (B3LYP/6-31G(d,p)) and time-dependent (TD) DFT, showing that the compounds will have significantly reduced propensity to decarboxylate from the first excited triplet state. In addition, docking studies were carried out for these new molecules to explore their activity and selectivity toward the two isoforms of the COX enzyme. The results show that most compounds have increased activity toward the COX enzymes, and in general are more selective toward the COX-2 target isoform. The results from this study suggest that the new modified molecules could be used in the future as NSAIDs with considerably reduced side effects.

  • 19.
    Musa, Klefah Abrahem Klefah
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Computational studies of photodynamic drugs, phototoxic reactions and drug design2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The most important criterion when designing new drugs or improving old ones in order to prevent side effects or at least diminish them is drug safety. Treatment of all diseases generally needs use of either topical application or systemic medications (transported in the blood) during a certain period of time. These treatments are associated with a number of adverse effects. Photosensitivity is one of those side effects, with phototoxicity as one of the photosensitivity disorders. This adverse side effect arises because of a reaction between UV or visible-light and the drug molecule, its active form or photoproduct(s). Due to phototoxic side effect, unexpected symptoms varying from just a simple rash to severe cutaneous affectations can appear. Furthermore, biomolecular damage occurs once the drug-light interaction takes place persistently and ends with cell death.

    Several drug families, such as over-the-counter drugs in the non-steroidal anti-inflammatory drug family of 2-arylpropionic acid derivatives, or prescription required fluoroquinolone drugs, have the capability to absorb mainly UV light radiation which in turn causes different phototoxic reactions by forming radical derivatives, reactive oxygen species or both. These may effect DNA, protein and lipid cell components leading to photogenotoxicity, photoallergy and lipid peroxidation, respectively. The photodegradation mechanisms of drugs belonging to the above mentioned families including ketoprofen, ibuprofen, flurbiprofen, naproxen, the active form of nabumetone, diclofenac and its main photoproduct, suprofen, tiaprofenic acid, naphazoline, norfloxacin and lomefloxacin are investigated in more detail in this thesis.

    The results obtained by computational density functional theory (DFT) and time-dependent-DFT (TD-DFT) are in line with experimental data available to date. The studies provide detailed insight into the molecular basis and understanding of the full photodegradation mechanisms of drugs mentioned above. This also plays an important role in preventing or at least reducing the phototoxic adverse effects by enabling the development of safe drugs in this area. Hence, new modified non-steroid anti-inflammatory molecules were designed by computational techniques. Obtained results suggest possibility of their future usage as pharmaceuticals with reduced photodegradation and cyclooxygenase 1 induced adverse side effects compared to the parent compounds.

    Delarbeten
    1. Mechanism of Photoinduced Decomposition of Ketoprofen
    Öppna denna publikation i ny flik eller fönster >>Mechanism of Photoinduced Decomposition of Ketoprofen
    2007 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, nr 8, s. 1735-1743Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.

    Ort, förlag, år, upplaga, sidor
    Washington, DC: American Chemical Society, 2007
    Nationell ämneskategori
    Teoretisk kemi Naturvetenskap Kemi
    Forskningsämne
    kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4100 (URN)10.1021/jm060697k (DOI)
    Tillgänglig från: 2007-11-01 Skapad: 2007-11-01 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Theoretical Study of Ibuprofen Phototoxicity
    Öppna denna publikation i ny flik eller fönster >>Theoretical Study of Ibuprofen Phototoxicity
    2007 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, nr 46, s. 13345-13352Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C−C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

    Ort, förlag, år, upplaga, sidor
    Washington, DC: American Chemical Society, 2007
    Nyckelord
    ibuprofen, phototoxicity, degradation, decarboxylation, reactive oxygen species, TD-DFT
    Nationell ämneskategori
    Teoretisk kemi Kemi
    Forskningsämne
    kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4113 (URN)10.1021/jp076553e (DOI)17958415 (PubMedID)
    Tillgänglig från: 2007-12-17 Skapad: 2007-12-17 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen
    Öppna denna publikation i ny flik eller fönster >>Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen
    2009 (Engelska)Ingår i: Journal of Photochemistry and Photobiology A: Chemistry, ISSN 1010-6030, E-ISSN 1873-2666, Vol. 202, nr 1, s. 48-56Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The photodegradation mechanism of the widely used non-steroidal anti-inflammatory drug 2-(4-phenyl-3-fluorophenyl) propanoic acid, Flurbiprofen, and its photochemical and photophysical properties have been investigated by means of computational quantum chemistry at the DFT-B3LYP/6-31G(d,p) level. Comparison of computed and experimental singlet and triplet–triplet absorption spectra point to that most experiments, using a range of different solvents, are conducted on the neutral, protonated form of Flurbiprofen. The deprotonated acid, which should dominate at physiological pH, shows no sign of decarboxylation from the lowest singlet excited states, whereas from its first excited triplet state this should readily occur by passing over an energy barrier of <0.5 kcal/mol. Further reactions in the proposed photodegradation mechanism, after decarboxylation, as well as the probability for reactive oxygen species formation are discussed in detail. The generation of the corresponding peroxyl radical from the decarboxylated radical and molecular oxygen is strictly exergonic and occurs without barrier under aerobic conditions. The thus formed peroxyl radical will in turn be capable of initiating propagating lipid peroxidation processes.

    Ort, förlag, år, upplaga, sidor
    Amsterdam: Elsevier, 2009
    Nationell ämneskategori
    Naturvetenskap Kemi Miljövetenskap
    Forskningsämne
    Miljökemi
    Identifikatorer
    urn:nbn:se:oru:diva-6319 (URN)10.1016/j.jphotochem.2008.11.010 (DOI)000263500000007 ()2-s2.0-58249098792 (Scopus ID)
    Tillgänglig från: 2009-04-21 Skapad: 2009-04-21 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Theoretical Study of the Phototoxicity of Naproxen and the Active Form of Nabumetone
    Öppna denna publikation i ny flik eller fönster >>Theoretical Study of the Phototoxicity of Naproxen and the Active Form of Nabumetone
    2008 (Engelska)Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, nr 43, s. 10921-10930Artikel i tidskrift (Refereegranskat) Published
    Ort, förlag, år, upplaga, sidor
    Washington, DC: American Chemical Society, 2008
    Nationell ämneskategori
    Naturvetenskap Kemi
    Forskningsämne
    kemi
    Identifikatorer
    urn:nbn:se:oru:diva-6318 (URN)10.1021/jp805614y (DOI)
    Tillgänglig från: 2009-04-21 Skapad: 2009-04-21 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    5. Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct
    Öppna denna publikation i ny flik eller fönster >>Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct
    2009 (Engelska)Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, nr 22, s. 4601-4610Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Diclofenac (DF) is a widely used non-steroid anti-inflammatory drug, associated with a range of side effects. The phototoxicity of DF is studied herein employing computational quantum chemistry at the B3LYP/6-31G(d,p) level of theory. The results show that the drug readily absorbs radiation from the UV-region. The deprotonated form spontaneously dechlorinates from its triplet state leading to ring closure and formation of an active photoproduct: chlorocarbazole acetic acid, CCA. The formed CCA is also photodegraded easily from its deprotonated triplet state. Photodegradation routes of deprotonated CCA are decarboxylation (barrier less than 4.5 kcal mol(-1)) and dechlorination (barrier around 6.2 kcal mol(-1)). The energy barrier required for dechlorination to take place from the neutral from is about 20 kcal mol(-1). The differences between the molecular orbitals of the neutral and the deprotonated forms of DF and CCA and spectra obtained using time-dependent density-functional theory (TD-DFT), in addition to the different radical and oxygenated intermediate species formed during the photodegradation mechanism, are discussed in more detail. The theoretical results obtained herein are in line with the experimental results available to date.

    Nationell ämneskategori
    Kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:oru:diva-13296 (URN)10.1039/b900144a (DOI)000266587300022 ()
    Tillgänglig från: 2011-01-14 Skapad: 2011-01-11 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    6. Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties: Suprofen and Tiaprofenic Acid
    Öppna denna publikation i ny flik eller fönster >>Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties: Suprofen and Tiaprofenic Acid
    2009 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, nr 32, s. 11306-11313Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The photodegradation of nonsteroid anti-inflammatory drugs suprofen, 2-[4-(2-thienoyl)phenyl]propionic acid, and tiaprofenic acid, 2-(5-benzoyl-2-thienyl)propanoic acid, is studied by means of density functional theory. Besides the redox properties of the neutral species, we report on absorption spectra and degradation pathways involving excitation, intersystem crossing to the T-1 state. and spontaneous decarboxylation of the deprotonated species of each drug. The energetics and properties of the suprofen and tiaprofenic acid systems are found to be very similar to those of the highly photolabile benzyl analogue ketoprofen. Mechanisms leading to the formation of a closed-shell decarboxylated ethyl species, as well as peroxyl radicals capable of initiating lipid peroxidation reactions, are discussed.

    Nationell ämneskategori
    Kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:oru:diva-13254 (URN)10.1021/jp904171p (DOI)000268661100033 ()
    Tillgänglig från: 2011-01-17 Skapad: 2011-01-11 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    7. Theoretical assessment of naphazoline redoxchemistry and photochemistry
    Öppna denna publikation i ny flik eller fönster >>Theoretical assessment of naphazoline redoxchemistry and photochemistry
    2007 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, nr 15, s. 3977-3981Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The imidazoline derivative naphazoline (2-(1-naphtylmethyl)-2-imidazoline) is an α2-adrenergic agonist used as non-prescription eye and nasal preparations. Besides its functionality in generating vascoconstriction and decongestion in the patient, the toxicity, ROS generating capability, and recently also possible antioxidant capacity of the compound have been reported in the literature. In the current work the structural and electronic features of the drug are explored, using computational chemical tools. Electron affinities, ionization potentials, and excitation energies are reported, as well as charge and spin distributions of various forms of the drug. The difference in photochemical behavior between the protonated and unprotonated (basic) species is explained by the molecular orbital distributions, allowing for efficient excitation quenching in the basic structure but clear naphthalene to imidazolene charge transfer upon HOMO→ LUMO excitation in the protonated form, enabling larger intersystem crossing capability to the imidazole localized excited triplet and a resulting higher singlet oxygen quantum yield.

    Ort, förlag, år, upplaga, sidor
    Washington, DC: American Chemical Society, 2007
    Nyckelord
    Molecular Structure, Naphazoline, Oxidation-Reduction, Photochemistry, Density functional theory
    Nationell ämneskategori
    Teoretisk kemi Naturvetenskap Kemi
    Forskningsämne
    kemi
    Identifikatorer
    urn:nbn:se:oru:diva-4105 (URN)10.1021/jp070207f (DOI)17388561 (PubMedID)
    Tillgänglig från: 2007-11-02 Skapad: 2007-11-02 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    8. Theoretical assessment of norfloxacin redox and photochemistry
    Öppna denna publikation i ny flik eller fönster >>Theoretical assessment of norfloxacin redox and photochemistry
    2009 (Engelska)Ingår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, nr 40, s. 10803-10810Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydo-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli c acid, NOR, is an antibiotic drug from the fluoroquinoline family. The different protonation states of this drug formed throughout the pH range is studied by means of density functional theory (DFT) and the spectra of the NOR species computed using time-dependent DFT. Details about their photochemistry are obtained from investigating the highest occupied and lowest unoccupied molecular orbitals. The predominant species under physiological pH, the zwitterion, is the most photoliable one, capable of producing singlet oxygen or/and superoxide radical anions from its triplet state. In addition, the main photodegradation step, defluorination, occurs more easily from this species compared with the other forms. The defluorination from the excited triplet state requires passing a barrier of 16.3 kcal/mol in the case of the zwitterion. The neutral and cationic forms display higher transition barriers, whereas the reaction path of defluorination is completely endothermic for the anionic species. The theoretical results obtained herein are in line with previous experimental data.

    Nationell ämneskategori
    Kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:oru:diva-13209 (URN)10.1021/jp904671s (DOI)000270362900026 ()
    Tillgänglig från: 2011-01-17 Skapad: 2011-01-11 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    9. Photophysical and photochemical properties and photodehalogenation of antibiotic drug lomefloxacin
    Öppna denna publikation i ny flik eller fönster >>Photophysical and photochemical properties and photodehalogenation of antibiotic drug lomefloxacin
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Fysikalisk kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:oru:diva-15445 (URN)
    Tillgänglig från: 2011-05-02 Skapad: 2011-05-02 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
    10. New non-steroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
    Öppna denna publikation i ny flik eller fönster >>New non-steroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Fysikalisk kemi
    Forskningsämne
    Kemi
    Identifikatorer
    urn:nbn:se:oru:diva-15446 (URN)
    Tillgänglig från: 2011-05-02 Skapad: 2011-05-02 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
  • 20. Schyman, Patric
    et al.
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Zhang, Ru bo
    Laaksonen, Aatto
    Hydroxyl radical - thymine adduct induced DNA damages2008Ingår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 458, nr 1-3, s. 186-189Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA damages caused by a 5-hydroxy-5,6-dihydrothymine-6-yl radical (5-OHT-6yl) abstracting a C20 hydrogen from a neighboring sugar (inter-H abstraction) have been theoretically investigated using hybrid DFT in gas phase and in water solution. The inter-H abstraction was here shown to be comparable in energy (24 kcal mol 1) with the intra-H abstraction in which the 5-OHT-6yl abstracts a C20 hydrogen from its own sugar. The effect of a neutrally or a negatively charged phosphate group was also studied and the results show no significant impact on the activation energy of the hydrogen abstraction whereas base release and strand break reactions are affected.

  • 21. Schyman, Patric
    et al.
    Zhang, Ru bo
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Laaksonen, Aatto
    Hydrogen Abstraction from Deoxyribose by a Neighbouring Uracil-5-yl Radical2007Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 9, s. 5975-5979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hydrogen abstraction from the C1 and C2 positions of deoxyadenosine by a neighbouring uracil-5-yl radical in the 5-AU-3 DNA sequence is explored using DFT. This hydrogen abstraction is the first step in a sequence leading to single or double strand break in DNA. The uracil-5-yl radical can be the result of photolysis or low-energy electron (LEE) attachment. If the radical is produced by photolysis the neighbouring adenine will become a cation radical and if it is produced by LEE the adenine will remain neutral. The hydrogen abstraction reactions for both cases were investigated. It is concluded that it is possible for the uracil-5-yl to abstract hydrogen from C1 and C2. When adenine is neutral there is a preference for the C1 site and when the adenine is a radical cation the C2 site is the preferred. If adenine is positively charged, the rate-limiting step when abstracting hydrogen from C1 is the formation of an intermediate crosslink between uracil and adenine. This crosslink might be avoided in dsDNA, making C1 the preferred site for abstraction.

  • 22.
    Sugunan, Abhilash
    et al.
    Center of Excellence in Nanotechnology, School of Engineering and Technology, Asian Institute of Technology, Pathumthani, Thailand .
    Melin, Petter
    Department of Microbiology Swedish, University of Agricultural Sciences, Uppsala, Sweden.
    Schnürer, Johan
    Department of Microbiology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Hilborn, Jons G.
    Department of Material Chemistry, Angstrom Laboratory, Uppsala University, Uppsala, Sweden.
    Dutta, Joydeep
    Center of Excellence in Nanotechnology, School of Engineering and Technology, Asian Institute of Technology, Pathumthani, Thailand.
    Nutrition-driven assembly of colloidal nanoparticles: Growing fungi assemble gold nanoparticles as microwires2007Ingår i: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 19, nr 1, s. 77-81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The use of a living fungus to 'actively' assemble presynthesized gold nano-particles over its hyphae, resulting in conducting microstructures (see figure), is reported. This physiologically (nutrition) driven process of colloidal self-organization avoids the need for sophisticated DNA/protein chemistry for facilitating interfacing with biological surfaces. The obtained gold-laden microstructures can be modified into flat ribbonlike or tubular morphologies by simple post-formation processing.

  • 23.
    Tian, Boxue
    et al.
    National University of Ireland, Galway, Ireland.
    Strid, Åke
    Örebro universitet, Akademin för naturvetenskap och teknik.
    Eriksson, Leif A.
    National University of Ireland, Galway, Ireland.
    Catalytic roles of active-site residues in 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase: an ONIOM/DFT study2011Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, nr 8, s. 1918-1926Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The catalytic mechanism of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) has been systematically studied using DFT and ONIOM(DFT:MM) methods. MHPCO catalyzes the hydroxylation and subsequent ring-opening of the aromatic substrate MHPC to give the aliphatic product R-(N-acetylaminomethylene)succinic acid (AAMS). Our calculations show that the active-site residues Arg211 and Tyr223 have a minor effect on the reaction, while the peptide bond of Pro295-Ala296, the side chain of Tyr82 and several crystal water molecules affect the reaction energy profile considerably. Both DFT and ONIOM calculations show that the ring-opening pathway B, in which an epoxy transition state is formed, is more favored than the direct C2-C3 cleavage pathway A. Different QM/MM partitioning schemes have been used to study the enzymatic reaction, and the results show that both the reaction barriers for the hydroxylation and the ring-opening pathways are sensitive to the QM/MM partitioning.

  • 24.
    Wu, Min
    et al.
    University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Leif A
    University of Gothenburg, Gothenburg, Sweden.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Theoretical prediction of the protein-protein interaction between Arabidopsis thaliana COP1 and UVR82013Ingår i: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 132, nr 7, artikel-id UNSP 1371Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In plants, ultraviolet-B radiation (280-315 nm) regulates gene expression and plant morphology through the UV RESPONSE LOCUS 8 (UVR8) photoreceptor. The first signaling event after quantal absorbance is the interaction of the UVR8 C-terminus with the E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1). The nature of the interaction between these two proteins is hitherto unknown. A protein homology model of the Arabidopsis thaliana COP1 seven bladed propeller WD40 repeat domain and de novo folds of the C-terminal 27 amino acid (amino acids 397-423) peptide of Arabidopsis UVR8 (UVR8397-423) is herein reported. Using a theoretical computational docking protocol, the interaction between COP1 and UVR8 was predicted. A core motif was identified in UVR8397-423 comprising adjacent hydrophobic residues V410 and P411 together with a charged residue D412, homologous to corresponding motifs in other COP1-binding proteins, such as ELONGATED HYPOCOTYL 5 (HY5), cryptochrome 1 (CRY1), and salt tolerance proteins STO/STH. The protein-protein interaction between the COP1 WD40 repeat domain and UVR8397-423 reveal binding within a region of COP1 overlapping the binding site for HY5 and the other COP1-interacting proteins. This study provides a framework for understanding docking between UVR8 and COP1, which in turn gives clues for experimental testing of UVR8/COP1 interaction.

  • 25.
    Wu, Min
    et al.
    Chalmers University of Technology, Gothenburg, Sweden.
    Farkas, Daniel
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; School of Science and Technology, Örebro University, Örebro, Sweden.
    Eriksson, Leif A.
    University of Gothenburg, Gothenburg, Sweden.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Proline 411 biases the conformation of the intrinsically disordered plant UVR8 photoreceptor C27 domain altering the functional properties of the peptide2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 818Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    UVR8 (UV RESISTANCE LOCUS 8) is a UV-B photoreceptor responsible for initiating UV-B signalling in plants. UVR8 is a homodimer in its signalling inactive form. Upon absorption of UV radiation, the protein monomerizes into its photoactivated state. In the monomeric form, UVR8 binds the E3 ubiquitin ligase COP1 (CONSTITUTIVELY PHOTOMORPHOGENIC 1), triggering subsequent UV-B-dependent photomorphogenic development in plants. Recent in vivoexperiments have shown that the UVR8 C-terminal region (aa 397-423; UVR8C27) alone is sufficient to regulate the activity of COP1. In this work, CD spectroscopy and NMR experiments showed that the UVR8C27domain was non-structured but gained secondary structure at higher temperatures leading to increased order. Bias-exchange metadynamics simulations were also performed to evaluate the free energy landscape of UVR8C27. An inverted free energy landscape was revealed, with a disordered structure in the global energy minimum. Flanking the global energy minimum, more structured states were found at higher energies. Furthermore, stabilization of the low energy disordered state was attributed to a proline residue, P411, as evident from P411A mutant data. P411 is also a key residue in UVR8 binding to COP1. UVR8C27is therefore structurally competent to function as a molecular switch for interaction of UVR8 with different binding partners since at higher free energies different structural conformations are being induced in this peptide. P411 has a key role for this function.

  • 26.
    Wu, Min
    et al.
    University of Gothenburg, Gothenburg, Sweden.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Eriksson, Leif A
    University of Gothenburg, Gothenburg, Sweden.
    Interactions and Stabilities of the UV RESISTANCE LOCUS8 (UVR8) protein dimer and its key mutants2013Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 53, nr 7, s. 1736-1746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dimeric UVR8 protein is a ultraviolet-B radiation (280-315 nm) photoreceptor responsible for the first step in UV-B regulation of gene expression in plants. Its action comprises the actual absorption of the UV quanta by a tryptophan array at the protein-protein interface, followed by monomerisation, and subsequent aggregation with downstream signaling components. A crystal structure of the Arabidopsis thaliana tryptophan-rich wild type UVR8 protein dimer was recently published, showing the presence of several salt bridges involving arginines R146, R286, R338 and R354. In this work, molecular dynamics simulations in conjunction with umbrella sampling was used to calculate the binding free energy for the wild type UVR8 dimer and three of its mutants (R286A, R338A and R286A/R338A), in order to verify whether the key mutants are able to disrupt the dimeric structure as indicated experimentally.

  • 27.
    Wu, Min
    et al.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Eriksson, Leif A
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Photochemical reaction mechanism of UV-B-induced monomerization of UVR8 dimers as the first signaling event in UV-B-regulated gene expression in plants2014Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, s. 951-965Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Arabidopsis thaliana UV RESISTANCE LOCUS8 (UVR8) protein has been identified to specifically mediate photomorphogenic UV-B responses by acting as a UV-B photoreceptor. The dimeric structure of the UVR8 protein dissociates into signaling–active monomers upon UV-B exposure, and the monomers rapidly interact with downstream signaling components to regulate gene expression. UVR8 monomers revert to dimers in the absence of UV-B radiation, thereby reversing transcription activation. UVR8 amino acid residues W233 and W285 have been identified to play critical roles in the UVR8 dimer for the response to UV-B irradiation. In the present work, the photo-reaction mechanism for UVR8 monomerization is explored using quantum chemical cluster calculations, and evaluated by molecular dynamics simulations using the wild type UVR8 dimer and novel force field parameters developed for intermediate radicals formed in the photochemical process. Three different models are investigated, which show that the preferred mechanism for UVR8 monomerization involves electron transfer from residue W233 to W285 and onwards to R338 initiated by UV-B irradiation, coupled to simultaneous proton transfer from W233 to D129 leading to the formation of protonated D129, a deprotonated W233 radical and a neutral R338 radical.. Due to the formation of the neutral R338 radical, salt bridges involving this residue are disrupted together with the concomitant interruption of several other key salt bridges R286-D96, R286-D107, R338-D44, R354-E43 and R354-E53. The resulting large decrease in protein-protein interaction energy arising from this sequence of events lead to the monomerization of the UVR8 dimer. The mechanism presented is in accord with all experimental data available to date.

  • 28. Zhang, Ru Bo
    et al.
    Zhang, Ke
    Eriksson, Leif A.
    Örebro universitet, Institutionen för naturvetenskap.
    Theoretical studies of damage to 3'-uridine monophosphate induced by electron attachment2008Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, nr 9, s. 2850-2856Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low-energy electrons (LEE) are well known to induce nucleic acid damage. However, the damage mechanisms related to charge state and structural features remain to be explored in detail. In the present work, we have investigated the N1-glycosidic and C3'-O(P) bond ruptures of 3'-UMP (UMP=uridine monophosphate) and the protonated form 3'-UMPH with -1 and zero charge, respectively, based on hybrid density functional theory (DFT) B3 LYP together with the 6-31+G(d,p) basis set. The glycosidic bond breakage reactions of the 3'UMP and 3'UMPH electron adducts are exothermic in both cases, with barrier heights of 19-20 kcal mol(-1) upon inclusion of bulk solvation. The effects of the charge state on the phosphate group are marginal, but the C2'-OH group destabilizes the transition structure of glycosidic bond rupture of 3'-UMPH in the gas phase by approximately 5.0 kcal mol(-1). This is in contrast with the C3'-O(P) bond ruptures induced by LEE in which the charge state on the phosphate influences the barrier heights and reaction energies considerably. The barrier towards C3'-O(P) bond dissociation in the 3'UMP electron adduct is higher in the gas phase than the one corresponding to glycosidic bond rupture and is dramatically influenced by the C2'-OH group and bulk salvation, which decreases the barrier to 14.7 kcal mol(-1). For the C3'-O(P) bond rupture of the 3'UMPH electron adduct, the reaction is exothermic and the barrier is even lower, 8.2 kcal mol(-1), which is in agreement with recent results for 3'-dTMPH and 5'-dTMPH (dTMPH=deoxythymidine monophosphate). Both the Mulliken atomic charges and unpaired-spin distribution play significant roles in the reactions

1 - 28 av 28
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf