Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides

Yang Y (2008)
Bielefeld (Germany): Bielefeld University.

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Bielefeld Dissertation | English
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Supervisor
Sewald, Norbert (Prof. Dr.)
Abstract
Biochemical processes within a cell or an organism are usually induced by molecular interaction and recognition events. One major aim of drug discovery is to identify bioactive molecular structures that can be used to sufficiently interfere with such molecular interaction processes and thereby positively influence and eventually cure a disease. Antagonists which prohibit the interactions between naturally occurring ligands and their protein receptors could be represented as good drug candidates. Low molecular weight ligands can interact with macromolecular target through covalent and noncovalent interactions. Noncovalent binding is characterized by equilibrium thermodynamics. Important noncovalent interactions are hydrogen bonds, ionic interactions and hydrophobic contacts. Steric and electronic complementarity between protein receptor and low molecular ligand seem to be the most important prerequisite to allow a tightly and selectively association. In almost any drug discovery project based on known biochemical target there exists some structural starting point for ligand design. In cases where the structure of protein receptor is available, diverse powerful computer-aided tools could be utilized to rationally design the ligand, such as molecular modeling tools for visualization and analysis, extraction of 3D structures from databases, construction of 3D models using force fields and molecular dynamics methods, and docking of 3D models to protein cavities. However, if the structure of protein receptor is unavailable, which is the case to many projects, the scope of utilization of computer-aided tools mentioned above would be hugely limited. Under these circumstances, more attention is supposed to be drawn upon the structure of the corresponding naturally occurring ligand. If the binding moiety could be determined putatively by comparison of the similarity with related homologous ligands, or ideally, confirmed experimentally, rational ligand design could thus be realized by imitating this binding domain, both its primary sequence and secondary structure. Ligand library could be established by specific site-mutation. The lead structure could be figured out by screening the members of the referred library, which contains ligands with diverse binding motifs or secondary structures. Among low molecular weight ligands short peptides stand out as good candidates. The peptide-protein interaction is an ideal subject for the rational design of inhibitor. Until now, innumerable peptides with a variety of biological and physiological effects have been detected, isolated, characterized and mostly synthesized. A number of very important physiological and biochemical functions of life are influenced by peptides. Peptides influence cell-cell communication upon interaction with receptors and are involved in a number of biochemical processes. Another advantage of peptide ligands results from their tailored conformations by incorporating special amino acid residues such as D-amino acids and N-alkylated amino acids, or by treating the peptide with certain synthetic mutations such as cyclization. In this project, integrin [alpha]3[beta]1, which is a member of the membrane protein integrin family, is chosen as the target for inhibition. The binding of integrin [alpha]3[beta]1 with its naturally occurring ligand invasin could lead to the internalization of bacteria Yersinia Sp., which is pathogenic to humans. The inhibition of this adhesion by synthetic peptides therefore possesses evident medical applications. The interaction between peptides and minerals in organisms presents us the amazing phenomenon of biomineralization, which is regarded as the site- and manner-selective nucleation of minerals in organisms. Again, the designed peptides which mimic these abstracted natural macromolecular templates in the organism such as mollusks could be utilized to decipher this mysterious process.
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Yang Y. Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides. Bielefeld (Germany): Bielefeld University; 2008.
Yang, Y. (2008). Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides. Bielefeld (Germany): Bielefeld University.
Yang, Y. (2008). Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides. Bielefeld (Germany): Bielefeld University.
Yang, Y., 2008. Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides, Bielefeld (Germany): Bielefeld University.
Y. Yang, Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides, Bielefeld (Germany): Bielefeld University, 2008.
Yang, Y.: Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides. Bielefeld University, Bielefeld (Germany) (2008).
Yang, Yi. Molecular recognition of integrin [alpha]3[beta]1 and inorganic compounds by tailor-made peptides. Bielefeld (Germany): Bielefeld University, 2008.
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