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Henschel, Henning
Publications (10 of 15) Show all publications
Karlsson, B. C. G., Olsson, G. D., Friedman, R., Rosengren, A. M., Henschel, H. & Nicholls, I. A. (2013). How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation. Journal of Physical Chemistry B, 117(8), 2384-2395
Open this publication in new window or tab >>How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation
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2013 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 8, p. 2384-2395Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-24761 (URN)10.1021/jp400264x (DOI)000315707900018 ()23373529 (PubMedID)2-s2.0-84874640546 (Scopus ID)
Available from: 2013-03-12 Created: 2013-03-12 Last updated: 2018-11-02Bibliographically approved
Nicholls, I. A., Andersson, H. S., Golker, K., Henschel, H., Karlsson, B. C. G., Olsson, G. D., . . . Wikman, S. (2013). Rational molecularly imprinted polymer design: theoretical and computational strategies. In: Ye, L (Ed.), Molecular Imprinting: Principles and Applications of Micro- and Nanostructured Polymers (pp. 71-104). London: Pan Stanford Publishing
Open this publication in new window or tab >>Rational molecularly imprinted polymer design: theoretical and computational strategies
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2013 (English)In: Molecular Imprinting: Principles and Applications of Micro- and Nanostructured Polymers / [ed] Ye, L, London: Pan Stanford Publishing, 2013, p. 71-104Chapter in book (Refereed)
Place, publisher, year, edition, pages
London: Pan Stanford Publishing, 2013
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-8867 (URN)2-s2.0-84974679377 (Scopus ID)9789814310994 (ISBN)
Available from: 2010-10-08 Created: 2010-10-08 Last updated: 2020-03-20Bibliographically approved
Henschel, H., Klöckner, J.-P., Nicholls, I. A. & Prosenc, M. H. (2012). Computational and structural studies on the complexation of cobalt(II) acetate by water and pyridine. Journal of Molecular Structure, 1007, 45-51
Open this publication in new window or tab >>Computational and structural studies on the complexation of cobalt(II) acetate by water and pyridine
2012 (English)In: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 1007, p. 45-51Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-16734 (URN)10.1016/j.molstruc.2011.09.050 (DOI)2-s2.0-84155172889 (Scopus ID)
Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08Bibliographically approved
Henschel, H., Prosenc, M. H. & Nicholls, I. A. (2011). A Density Functional Study on the Factors Governing Metal Catalysis of the Direct Aldol Reaction. Journal of Molecular Catalysis A: Chemical, 351, 76-80
Open this publication in new window or tab >>A Density Functional Study on the Factors Governing Metal Catalysis of the Direct Aldol Reaction
2011 (English)In: Journal of Molecular Catalysis A: Chemical, ISSN 1381-1169, E-ISSN 1873-314X, Vol. 351, p. 76-80Article in journal (Refereed) Published
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.

Keywords
Aldol reaction, Catalysis, Metal, Density functional calculation, C–C bond formation
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-16739 (URN)10.1016/j.molcata.2011.09.019 (DOI)2-s2.0-81155128672 (Scopus ID)
Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08Bibliographically approved
Henschel, H., Kirsch, N., Hedin-Dahlström, J., Whitcombe, M., Wikman, S. & Nicholls, I. A. (2011). Effect of the cross-linker on the general performance and temperature dependent behaviour of a molecularly imprinted polymer catalyst of a Diels-Alder reaction. Journal of Molecular Catalysis B: Enzymatic, 72(3-4), 199-205
Open this publication in new window or tab >>Effect of the cross-linker on the general performance and temperature dependent behaviour of a molecularly imprinted polymer catalyst of a Diels-Alder reaction
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2011 (English)In: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 72, no 3-4, p. 199-205Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-16742 (URN)10.1016/j.molcatb.2011.06.006 (DOI)2-s2.0-80052266366 (Scopus ID)
Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2018-05-18Bibliographically approved
Nicholls, I. A., Andersson, H. S., Golker, K., Henschel, H., Karlsson, B. C. G., Olsson, G. D., . . . Wikman, S. (2011). Rational Design of Biomimetic Molecularly Imprinted Materials: Theoretical and Computational Strategies for Guiding Nanoscale Structured Polymer Development. Analytical and Bioanalytical Chemistry, 400, 1771-1786
Open this publication in new window or tab >>Rational Design of Biomimetic Molecularly Imprinted Materials: Theoretical and Computational Strategies for Guiding Nanoscale Structured Polymer Development
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2011 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 400, p. 1771-1786Article, review/survey (Refereed) Published
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.

National Category
Theoretical Chemistry Organic Chemistry Analytical Chemistry Polymer Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-16276 (URN)10.1007/s00216-011-4935-1 (DOI)2-s2.0-84961983789 (Scopus ID)
Available from: 2011-12-21 Created: 2011-12-21 Last updated: 2020-03-20Bibliographically approved
Henschel, H., Karlsson, B. C. G., Rosengren, A. M. & Nicholls, I. A. (2010). Insights into the Isomerisation Mechanism of Warfarin. In: : . Paper presented at 22:nd Organic Chemistry Days (Organikerdagarna), Uppsala.
Open this publication in new window or tab >>Insights into the Isomerisation Mechanism of Warfarin
2010 (English)Conference paper, Published 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).

National Category
Organic Chemistry
Research subject
Natural Science, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-6711 (URN)
Conference
22:nd Organic Chemistry Days (Organikerdagarna), Uppsala
Available from: 2010-07-07 Created: 2010-07-07 Last updated: 2016-11-11Bibliographically approved
Henschel, H., Karlsson, B. C. G., Rosengren, A. M. & Nicholls, I. A. (2010). The Mechanistic Basis for Warfarin’s Structural Diversity and Implications for Its Bioavailability. Journal of Molecular Structure: THEOCHEM, 958, 7-9
Open this publication in new window or tab >>The Mechanistic Basis for Warfarin’s Structural Diversity and Implications for Its Bioavailability
2010 (English)In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 958, p. 7-9Article in journal (Refereed) Published
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.

Keywords
Density functional calculations, Molecular diversity, Reaction mechanisms, Transition states, Warfarin
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-7657 (URN)10.1016/j.theochem.2010.07.018 (DOI)2-s2.0-77956763892 (Scopus ID)
Available from: 2010-08-23 Created: 2010-08-23 Last updated: 2017-12-12Bibliographically approved
Nicholls, I. A., Karlsson, B. C. G., Rosengren, A. M. & Henschel, H. (2010). Warfarin: an environment-dependent switchable molecular probe. Journal of Molecular Recognition, 23(6), 604-608
Open this publication in new window or tab >>Warfarin: an environment-dependent switchable molecular probe
2010 (English)In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 23, no 6, p. 604-608Article in journal (Refereed) Published
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.

Keywords
warfarin, fluorescence, fluorescence lifetimes, organic solvents, molecular recognition, molecular probe, molecularly imprinted polymer, human serum albumin;HSA, colloidal silica, TCSPC
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-7954 (URN)10.1002/jmr.1058 (DOI)21031478 (PubMedID)2-s2.0-77956717111 (Scopus ID)
Available from: 2010-08-31 Created: 2010-08-31 Last updated: 2017-12-12Bibliographically approved
Nicholls, I. A., Karlsson, B. C. G., Andersson, H. S., Golker, K., Henschel, H., Olsson, G. D., . . . Wikman, S. (2009). Biomimetic Polymer Design. In: : . Paper presented at Scanbalt Forum Biomaterials Days, Kalmar.
Open this publication in new window or tab >>Biomimetic Polymer Design
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2009 (English)Conference paper, Published paper (Refereed)
National Category
Chemical Sciences
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-6756 (URN)
Conference
Scanbalt Forum Biomaterials Days, Kalmar
Available from: 2010-07-08 Created: 2010-07-08 Last updated: 2020-03-20Bibliographically approved
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