TY  - THES
T1  - A powerful combination of computational methods on the road toward potent non-steroidal inhibitors of steroidogenic enzymes involved in hormone-dependent diseases
A1  - Negri,Matthias
Y1  - 2010/08/20
N2  - Different computational methods have been applied to the development of non-steroidal inhibitors of steroidogenic enzymes for the treatment of hormone-sensitive diseases, like breast and prostate cancer and hypertension. A high-quality homology model of CYP17 was created and used for docking studies. Three binding modes were identified and SAR for different CYP17-inhibitor classes, substantiated by ab initio calculations, could be derived and used in further drug design leading to improved potency. Docking studies and ligand cluster analysis for a series of CYP19 inhibitors resulted in a binding mode, well explaining their different inhibitory potencies. The derived SAR were used in ongoing drug design, resulting so far in highly potent CYP19 inhibitors. The kinetic cycle of 17β-HSD1 was hypothesized based on biochemical data, analysis of the crystal structures and a multi-trajectory MD approach and provided insights in protein motion. These were translated into the drug design process. An ensemble docking study was performed for bis(hydroxyphenyl)-arenes, potent 17β-HSD1 inhibitors, and two conformation-dependent binding modes were identified. MD simulations and quantum-chemical calculations identified one of them as the more plausible, suggesting this class of compounds to dysfunction the enzyme dynamics. Two pharmacophore models were derived from CYP11B2 inhibitors and combined into a ligand- and structure-based approach, which led to a new class of potent CYP11B2 inhibitors.

KW  - Enzyminhibitor
KW  - Enzymkinetik
KW  - Cytochrome
KW  - CADEMO
KW  - CADD
KW  - Molekulardesign
KW  - Molekulardynamik
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2010/3284
ER  -