title: Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.
abstract: The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P. le A. Moro 5, 00185 Roma, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Ballante
authors.forename: Antonia
authors.initials: A
authors.lastname: Caroli
authors.forename: Richard B
authors.initials: RB
authors.lastname: Wickersham
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D030562:Databases, Protein; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; 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