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Thermodynamic evaluation of carbohydrate-lectin interactions

Lemme, Katrin. Thermodynamic evaluation of carbohydrate-lectin interactions. 2013, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10606

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Abstract

In the drug discovery process, the thermodynamics of protein-ligand interactions have recently received increasing attention. Particularly, changes in enthalpy and entropy provide insight into the driving forces of biomolecular interactions. Furthermore, the knowledge of the thermodynamic fingerprints of a series of ligand-receptor interactions facilitates the optimization of structure activity relationships. With isothermal titration calorimetry (ITC), the enthalpy change (deltaH°), dissociation constant (KD), and stoichiometry of the interaction (N) are directly accessible in a single experiment. Based on these values, the changes in free energy of binding (deltaG°) and entropy (deltaS°) can then be calculated. A favorable enthalpy term results from an overcompensation of the desolvation penalty by newly formed hydrogen bonds as well as electrostatic and dipole-dipole interactions. The entropy term describes the change in the degrees of freedom of a system. It consists of changes in solvation entropy, translational and rigid body rotational entropy, as well as entropy costs related to conformational changes.
Most reported thermodynamic studies on carbohydrate-recognizing proteins (lectins) concern plant lectins. However, human and bacterial lectins have recently gained increasing interest. One of these, the human lectin E-selectin plays a crucial role in leukocyte trafficking and is a key player in the early stages of inflammation; it is responsible for the rolling of leukocytes along the vascular endothelial surface, which is followed by their firm adhesion and extravasation to fight the inflammatory stimulus. The interaction of E-selectin with the minimal binding epitope of its physiological ligand, the so-called sLex tetrasaccharide, and mimetic antagonists thereof are characterized by a large favorable entropy term. The entropic benefit is mainly related to the release of water molecules from the large binding interface into bulk water, as well as to the high degree of pre-organization of sLex. The replacement of those parts of sLex not involved in binding by lipophilic moieties resulted in improved binding enthalpy (chapter 2.1.1). The lectin DC-SIGN (DC-specific intracellular adhesion molecule-3 grabbing nonintegrin) plays a crucial role in the immune system and is involved in the defense mechanism against pathogens. The millimolar binding affinities of DC-SIGN antagonists are the result of a favorable enthalpic term opposed by an entropic penalty (chapter 2.1.2). In contrast, antagonists binding to Siglec-4 (MAG) and Siglec-2 (CD22), inhibitory proteins of the central nervous system and the immune system, respectively, bind with nanomolar binding affinities. The driving force for their binding results from a strong enthalpic contribution and a varying entropic term, indicating optimal exploitation of the binding pocket (chapters 2.2.1 and 2.2.2). Finally, low nanomolar binding affinities were also found for FimH antagonists. FimH antagonists prevent the initial attachment of uropathogenic Escherichia coli to host cells and therefore offer a potential therapeutic approach for the prevention and/or treatment of urinary tract infection. They exhibit favorable enthalpic contributions and are accompanied by only small entropic penalties, although some of the antagonists are equipped with highly flexible aglycones (chapter 2.3.1).
In summary, the largely differing thermodynamics of the investigated carbohydrate-lectin interactions have contributed helpful insight into the driving forces of these interactions.
Advisors:Ernst, Beat
Committee Members:Klebe, Gerhard
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Lemme, Katrin and Ernst, Beat
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:10606
Thesis status:Complete
Number of Pages:217 Bl.
Language:English
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:51
Deposited On:28 Nov 2013 10:17

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