TY  - THES
T1  - Characterization of protein-ligand interactions : the role of thermodynamic and structural data in the drug discovery process
A1  - Klein,Tobias
Y1  - 2012/09/19
N2  - Comparing biological activities and thermodynamic profiles obtained for one compound toward proteins, differing only in few residues is a promising strategy to increase the knowledge of protein-ligand interactions and active site topologies thereby enabling rational drug design.
For this purpose, wild type proteins and their mutants carrying a set of point mutations can be used. Such an approach was applied in the present study to guide the development of small-molecule antagonists targeting PqsR, a novel target to limit Pseudomonas aeruginosa pathogenicity. It resulted in two chemically divers fragments with antagonistic activity and provided insights into their binding modes. The latter can be used to assist fragment optimization and therefore the identified PqsR antagonists are promising scaffolds for further drug design efforts against this important pathogen.
Alternatively, proteins from various species, which are highly conserved in sequence and differ only in few residues, might be considered. This line of attack was also utilized employing human and marmoset monkey 17β-HSD1, a promising target for the treatment of estrogen-dependent diseases. By means of in silico methods a better understanding of 17β-HSD1 active site topologies and inhibitor binding modes was achieved that guided the elaboration of a lead compound. 
The described strategy was successfully applied for hit identification and lead optimization reflecting its benefit in drug design.
KW  - Pharmazeutische Chemie
KW  - Wirkstoff-Rezeptor-Bindung
KW  - Infektionskrankheit
KW  - Pseudomonas aeruginosa
KW  - Arzneimitteldesign
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2012/4962
ER  -