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Le Touquet – Paris-Plage, France

Audisio D.,University Paris - Sud | Messaoudi S.,University Paris - Sud | Ijjaali I.,Aureus Pharma | Dubus E.,Aureus Pharma | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2010

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. © 2010 Elsevier Masson SAS. All rights reserved. Source

Faure P.,Aureus Pharma | Dubus E.,Aureus Pharma | Ijjaali I.,Aureus Pharma | Morlire C.,Aureus Pharma | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2010

A large number of chemical structures that interact with G-protein coupled receptors (GPCRs) have been disclosed in patents or published papers. Most of these compounds are selective for a given protein target; however, it is well recognized that some GPCR-drugs interact with multiple targets. Using a literature database, we have identified compounds that act on different GPCRs. These protein targets are usually divided in three main classes, A, B and C, based on sequence similarity, but they can also be grouped pharmacologically based on endogenous ligand characteristics. In this paper, we specifically focus on compounds able to recognize two different classes or different pharmacological clusters within the same class. Despite the large number of GPCR ligands described in the literature, we identified a limited number of molecules acting on both classes A and B, only few acting on classes A and C and none acting on class B and C receptors. A search for bi- or multi-potent compounds exhibiting activities on different pharmacological clusters of class A receptors revealed cases of cross reactivity, the most frequent concerning amine and peptide receptor clusters. © 2010 Elsevier Masson SAS. All rights reserved. Source

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