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  • 1.
    Henschel, Henning
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Insights into the Isomerisation Mechanism of Warfarin2010Conference paper (Refereed)
    Abstract [en]

    Warfarin is one of the most commonly used drugs in anticoagulent therapy. Notwithstanding its wide use, achieving correct dosage is often a major challenge due to its narrow therapeutic window.[1] The bioavailability of warfarin is believed to be greatly influenced by the environment-dependent composition of the ensemble of isomers present. While the different structures of warfarin have been discussed in earlier publications,[2] details of the mechanism underlying the formation of the cyclic hemiacetal (Figure 1) had not yet been investigated.

    Figure 1. Cyclization reaction of warfarin.

    Figure 2. Transition state in presence of one water molecule.

     

    We have now studied the reaction by means of density functional calculations. Comparison of results from calculations performed on the isolated warfarin molecule and in presence of water molecules (compare Figure 2) highlight the importance of intermolecular interactions in the key proton transfer step for the reaction to proceed. A viable model for the mechanism underlying the isomerisation shall be presented.

     

     

    References

    [1]             J. Ansell, J. Hirsh, L. Poller, H. Bussey, A. Jacobsen and E. Hylek, Chest, 126, 204S (2004).

    [2]            B. C. G. Karlsson, A. M. Rosengren, P. O. Andersson and I. A. Nicholls, J. Phys. Chem. B, 111,10520 (2007).

  • 2.
    Henschel, Henning
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The Mechanistic Basis for Warfarin’s Structural Diversity and Implications for Its Bioavailability2010In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 958, p. 7-9Article in journal (Refereed)
    Abstract [en]

    The anticoagulent drug warfarin exhibits chameleon-like isomerism, where the environment-dependent composition of the ensemble of structures greatly influences its bioavailability. Here, the mechanism of conversion between the major isomeric forms is studied. The dramatic differences in transition state energies, as determined by density functional calculations, highlight the necessity for the involvement of intermolecular interactions in the key proton transfer step. A viable model for the mechanism underlying the isomerization reactions is presented.

  • 3.
    Henschel, Henning
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Kirsch, Nicole
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hedin-Dahlström, Jimmy
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Whitcombe, Michael J
    Wikman, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nicholls, Ian Alan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Molecularly imprinted polymer catalysis of a Diels-Alder reaction2006Conference paper (Refereed)
  • 4.
    Henschel, Henning
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Kirsch, Nicole
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Hedin-Dahlström, Jimmy
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Whitcombe, MJ
    Wikman, Susanne
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effect of the cross-linker on the general performance and temperature dependent behaviour of a molecularly imprinted polymer catalyst of a Diels-Alder reaction2011In: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 72, no 3-4, p. 199-205Article in journal (Refereed)
    Abstract [en]

    Here we present a series of molecularly imprinted polymers capable of catalysing the Diels-Alder reaction between benzyl 1,3-butadienylcarbamate (1) and N,N-dimethyl acrylamide (2). The polymer systems studied here demonstrated an unusual cross-linker and temperature dependent behaviour, namely that polymer catalysis of the Diels-Alder reaction was lower at elevated temperature, in contrast to the solution reaction. Furthermore, not only was the catalytic activity significantly influenced by the choice of cross-linker, but in a similar fashion also the extent of the temperature effect, indicating a close relationship between catalysis and the observed inhibition. Molecular dynamics simulations of both the polymer systems studied were used to provide insight into the molecular background of transition state stabilisation, and differences in properties of the systems based on different cross-linkers.

  • 5.
    Henschel, Henning
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Klöckner, Jan-Peter
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Prosenc, Marc H.
    Computational and structural studies on the complexation of cobalt(II) acetate by water and pyridine2012In: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 1007, p. 45-51Article in journal (Refereed)
    Abstract [en]

    Four different complexes of the cobalt(II) acetate–pyridine–water system were obtained as dominant species by crystallization from a series of dichloromethane and toluene solutions. The complexes were characterized by terms of X-ray crystal structure determination. Factors in solution properties leading to crystallization of certain complexes are discussed. Furthermore, trends in terms of structure and binding energies in a systematic series of mononuclear cobalt(II) complexes were studied using density functional calculations.

  • 6.
    Henschel, Henning
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Prosenc, Marc H.
    University of Hamburg, Germany.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    A Density Functional Study on the Factors Governing Metal Catalysis of the Direct Aldol Reaction2011In: Journal of Molecular Catalysis A: Chemical, ISSN 1381-1169, E-ISSN 1873-314X, Vol. 351, p. 76-80Article in journal (Refereed)
    Abstract [en]

    Density functional calculations are employed in the study of the C-C bond formation step of an aldol reaction in presence of a series of metals. Focus was placed on first row d-block metals that have been used in catalysis of direct aldol reactions. The obtained energy profiles are analysed in order to differentiate between factors governing catalysis. Results demonstrate a major influence of d-orbital occupation, and suggest some of the so far less commonly used metals as promising candidates for development of new catalytic systems.

  • 7.
    Karlsson, Björn C. G.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henschel, Henning
    Division of Atmospheric Sciences, Department of Physics, University of Helsinki, P.O. Box 64, Helsinki, Finland.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation2013In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 8, p. 2384-2395Article in journal (Refereed)
    Abstract [en]

    The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were −97 and −146 kJ·mol–1. Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin’s accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin’s structural diversity on the drug’s distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.

  • 8.
    Kirsch, Nicole
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hedin-Dahlström, Jimmy
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henschel, Henning
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Whitcombe, Michael J
    Wikman, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nicholls, Ian A.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Molecularly imprinted polymer catalysis of a Diels-Alder reaction2009In: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 58, no 1-4, p. 110-117Article in journal (Refereed)
    Abstract [en]

    A series of synthetic polymers were designed and synthesized for enhancing the rate of the Diels-Alder cycloaddition reaction of 1,3-butadiene carbamic acid benzyl ester (11) and N,N-dimethyl acrylamide (2), to yield the corresponding endo- (3) and exo- (4) reaction products. Putative transition state analogues (TSAs) for the endo- (5) and exo- (6) reaction pathways were used as templates for the synthesis of molecularly imprinted methacrylic acid (MAA)-divinylbenzene (DVB) copolymers. The polymer system utilized was selected based upon a series of (1)H NMR studies of complex formation between template and a functional monomer analogue (K(d) (app) approximate to 70 mM, d(8)-toluene, 293 K). Batch binding studies revealed that the imprinted polymers were selective for the TSA corresponding to the template used in the polymer synthesis. Studies on the influence of the polymers on the catalysis of the reaction of 1 and 2 demonstrated a 20-fold enhancement of the rate of the reaction relative to the solution reaction. A surprising temperature dependence of the reaction of 1 and 2 in the presence of the polymers was observed, which provides support for the role of template-functional monomer complexes in the catalysis of the Diels-Alder reaction.

  • 9.
    Kirsch, Nicole
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hedin-Dahlström, Jimmy
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henschel, Henning
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wikman, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nicholls, Ian Alan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Towards a MIP-based stereoselective Diels-Alderase2004Conference paper (Refereed)
  • 10.
    Nicholls, Ian A.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Andersson, Håkan S.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Charlton, Christy
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henschel, Henning
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Karlsson, Björn C. G.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Karlsson, Jesper G.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    O'Mahony, John
    Rosengren, Annika M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren, K. Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wikman, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Theoretical and Computational Strategies for Rational Molecularly Imprinted Polymer Design2009In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 25, no 3, p. 543-552Article in journal (Refereed)
    Abstract [en]

    The further evolution of molecularly imprinted polymer science and technology necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. A combination of the rapid growth in computer power over the past decade and significant software developments have opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers. 

  • 11.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Golker, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Henschel, Henning
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Shoravi, Siamak
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Wiklander, Jesper G.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Wikman, Susanne
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rational Design of Biomimetic Molecularly Imprinted Materials: Theoretical and Computational Strategies for Guiding Nanoscale Structured Polymer Development2011In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 400, p. 1771-1786Article, review/survey (Refereed)
    Abstract [en]

    In principle, molecularly imprinted polymer science and technology provides a means for ready access to nano-structured polymeric materials of predetermined selectivity. The versatility of the technique has brought it to the attention of many working with the development of nanomaterials with biological or biomimetic properties for use as therapeutics or in medical devices. Nonetheless, the further evolution of the field necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. The rapid growth in computer power and software over the past decade has opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers.

  • 12.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Andersson, Håkan S.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Golker, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henschel, Henning
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Shoravi, Siamak
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wiklander, Jesper G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wikman, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rational molecularly imprinted polymer design: theoretical and computational strategies2013In: Molecular Imprinting: Principles and Applications of Micro- and Nanostructured Polymers / [ed] Ye, L, London: Pan Stanford Publishing, 2013, p. 71-104Chapter in book (Refereed)
  • 13.
    Nicholls, Ian A.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Karlsson, Björn C. G.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Andersson, Håkan S.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Golker, Kerstin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henschel, Henning
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Olsson, Gustaf D.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    O'Mahony, John
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Orozovic, Kanita
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren, Annika M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren-Holmberg, Jenny P.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Shoravi, Siamak
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wiklander, Jesper G.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wikman, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Biomimetic Polymer Design2009Conference paper (Refereed)
  • 14.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Henschel, Henning
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Warfarin: an environment-dependent switchable molecular probe2010In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 23, no 6, p. 604-608Article in journal (Refereed)
    Abstract [en]

    The complex nature of the structure of the anticoagulant warfarin is reflected in the diversity of binding modes observed in warfarin–protein recognition systems. A series of theoretical, 1H-NMR and steady state and time resolved fluorescence spectroscopic studies, have been used to establish correlations between the molecular environment provided by various solvent systems and the relative concentrations of the various members of warfarin's ensemble of isomers. A consequence of these observations is that the judicious choice of solvent system or molecular environment of warfarin allows for manipulation of the position of the equilibrium between isomeric structures such as the hemiacetal and open phenol-keto forms, the latter even possible in a deprotonated form, where in each case unique spectroscopic properties are exhibited by the respective structures. Collectively, warfarin's capacity to adapt its structure as a function of environment in conjunction with the fluorescence behaviours of the various isomers together provide an environment-dependent molecular switch with reporter properties, which allows for the simultaneous detection of warfarin in different states with lifetimes spanning the range < 0.10–5.5 ns. These characteristics are here used to examine warfarin binding domains in a series of materials (solvents, protein, inorganic matrix and synthetic polymer). Moreover, these studies demonstrate the potential for using warfarin, or other switchable analogues thereof, as a tool for studying molecular level characteristics, for example local dielectricity. Copyright © 2010 John Wiley & Sons, Ltd.

  • 15.
    Wikman, Susanne
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henschel, Henning
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hedin-Dahlström, Jimmy
    Whitcombe, Michael
    Nicholls, Ian Alan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Molecularly imprinted polymer catalysis of a Diels-Alder reaction.2006Conference paper (Other academic)
1 - 15 of 15
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