TY  - THES
T1  - Computational design and analysis of binding pockets at protein-protein interaction interfaces
A1  - Eyrisch,Susanne
Y1  - 2009/11/06
N2  - Protein-protein interactions play a pivotal role in most biological processes. Especially their function in controlling apoptosis makes them to important drug targets. But in contrast to enzymes, the applicability of existing in silico methods assisting the design of small-molecule inhibitors is abated by the intrinsic properties of protein-protein interaction interfaces. The central problem is that in the absence of inhibitors, accessible binding pockets are lacking in this region. In this thesis, we present computational approaches for designing and analyzing binding pockets located at protein-protein interaction interfaces. We observed that transient pockets not accessible in the unbound crystal structures of proteins involved in protein-protein interactions are frequently open in alternative protein conformations. At the native binding site, pockets suitable for accommodating known inhibitors were observed. Based on these findings, we studied how these pocket openings occur and developed different protocols for detecting and designing such ligand binding pockets. If no information about the binding site is available, the surface of the entire protein is sampled and all transient pockets opening on the protein surface are identified. If the binding site is approximately known, pockets of predefined properties are algorithmically designed at the desired location. After validating the protocols using three model systems, we show their application to two test systems.
KW  - Arzneimitteldesign
KW  - Protein-Protein-Wechselwirkung
KW  - Computational chemistry
KW  - Docking protein
KW  - Molekulardynamik
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2009/2534
ER  -