Combined pharmacophore and structure-guided studies to identify diverse HSP90 inhibitors
| Autor: | Raveendra Dayam, Rambabu Gundla, Lakshmi Narasu, S. Vadivelan, Ramadevi Sanam, Nouri Neamati, Pavan Kumar Machiraju, Sarma A.R.P. Jagarlapudi, Sunita Tajne |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Cell Death biology Cell growth In silico Reproducibility of Results Antineoplastic Agents Computational biology Computer Graphics and Computer-Aided Design Combinatorial chemistry Hsp90 Docking (molecular) Cell Line Tumor Drug Design Chaperone (protein) Heat shock protein Materials Chemistry biology.protein Humans HSP90 Heat-Shock Proteins Drug Screening Assays Antitumor Physical and Theoretical Chemistry Pharmacophore Cytotoxicity Spectroscopy |
| Zdroj: | Journal of Molecular Graphics and Modelling. 28:472-477 |
| ISSN: | 1093-3263 |
| DOI: | 10.1016/j.jmgm.2009.11.002 |
| Popis: | Heat Shock Protein 90 (HSP90), an ATP-dependent molecular chaperone, has emerged as a promising target in the treatment of cancer. Inhibition of HSP90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. Many HSP90 inhibitors bind to the ATP-binding pocket, inhibit chaperone function, resulting in cell death. Recent clinical trials for treatment of cancer have put HSP90's importance into focus and have highlighted the need for full scale research into HSP90 related pathways. Here we report five novel HSP90 inhibitors which were identified by using pharmacophore models and docking studies. We used highly discriminative pharmacophore model as a 3D query to search against database of approximately 1 M compounds and cluster analysis results yielded 455 compounds which were further subjected for docking. Glide docking studies suggested 122 compounds as in silico hits and these compounds were further selected for the cytotoxicity assay in the HSP90-over expressing SKBr3 cell line. Of the 122 compounds tested, 5 compounds inhibited cell growth with an IC(50) value less than 50 microM. |
| Databáze: | OpenAIRE |
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