title: Hsp90 inhibitors, part 2: combining ligand-based and structure-based approaches for virtual screening application.
abstract: Hsp90 continues to be an important target for pharmaceutical discovery. In this project, virtual screening (VS) for novel Hsp90 inhibitors was performed using a combination of Autodock and Surflex-Sim (LB) scoring functions with the predictive ability of 3-D QSAR models, previously generated with the 3-D QSAutogrid/R procedure. Extensive validation of both structure-based (SB) and ligand-based (LB), through realignments and cross-alignments, allowed the definition of LB and SB alignment rules. The mixed LB/SB protocol was applied to virtually screen potential Hsp90 inhibitors from the NCI Diversity Set composed of 1785 compounds. A selected ensemble of 80 compounds were biologically tested. Among these molecules, preliminary data yielded four derivatives exhibiting IC50 values ranging between 18 and 63 μM as hits for a subsequent medicinal chemistry optimization procedure.
authors.affiliation: Department of Physics, Sapienza Università di Roma , P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Caroli
authors.forename: Flavio
authors.initials: F
authors.lastname: Ballante
authors.forename: Richard B
authors.initials: RB
authors.lastname: Wickersham
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
mesh_terms: D003198:Computer Simulation; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D054852:Small Molecule Libraries