Assessing the chemical diversity of an hsp90 database.
The 90-kDa heat shock protein (hsp90) has emerged as a new, promising target for cancer drug discovery. With the simultaneous disruption of a large range of oncogenic pathways, hsp90 inhibition results in either cytostasis or cell death. Diverse inhibitors of this molecular chaperone are currently under intensive study, and several have reached clinical trials. In the present work, patented and published structure-activity relationships on hsp90 inhibitors were organised in a database format that associates chemical structures with their biological activities. This hsp90 database contains 814 unique structures and, to our knowledge, is the most complete ever reported. With the aim to provide a general overview and evaluation of the chemical diversity of the ligands included in the dataset, a two-dimensional analysis was performed. A set of twenty-five topological molecular descriptors was calculated, allowing the emphasis of those that have higher importance for hsp90 active compounds, and for the three chemical scaffold families, geldanamycins, purines and pyrazole-isoxazoles. We have used a principal-component analysis (PCA) computational approach to analyse the 2D descriptor space of active and non-active hsp90 ligands. Furthermore, a fragment-based study highlighted the most frequently moieties represented in the active purine and pyrazole-isoxazole derivatives that are likely to be responsible for the observed biological activities.
Audisio
Davide
D
University Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France. davide.audisio@u-psud.fr
Messaoudi
Samir
S
Ijjaali
Ismail
I
Dubus
Elodie
E
Petitet
François
F
Peyrat
Jean-François
JF
Brion
Jean-Daniel
JD
Alami
Mouâd
M
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D025341:Principal Component Analysis; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D008024:Ligands; D011687:Purines; D011720:Pyrazoles; C031280:pyrazole; C030985:purine