title: Combined pharmacophore and structure-guided studies to identify diverse HSP90 inhibitors.
abstract: 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.
authors.affiliation: Division of Informatics, GVK Biosciences Pvt. Ltd., S-1, Phase-1, T.I.E. Balanagar, Hyderabad 500037, Andhra Pradesh, India. ramadevi.sanam@gvkbio.com
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Sanam
authors.forename: Sunita
authors.initials: S
authors.lastname: Tajne
authors.forename: Rambabu
authors.initials: R
authors.lastname: Gundla
authors.forename: S
authors.initials: S
authors.lastname: Vadivelan
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Machiraju
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Narasu
authors.forename: Sarma
authors.initials: S
authors.lastname: Jagarlapudi
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins