title: 3D-QSAR using pharmacophore-based alignment and virtual screening for discovery of novel MCF-7 cell line inhibitors.
abstract: The development of a novel approach for the prediction of antiestrogenic activity is described, bringing up to date a previous pharmacophore study. Software Phase has been used to derive a 3D-QSAR model based, as alignment rule, on a pharmacophore built on three compounds highly active against MCF-7 cell line. Five features comprised the pharmacophore: two hydrogen-bond acceptors, one hydrogen-bond donor, and two aromatic rings. The sequential 3D-QSAR yielded a test set q(2) equal to 0.73 and proved to be predictive with respect to an external test set of 21 compounds (r(2) = 0.69). The model was used to detect new MCF-7 inhibitors through 3D-database searching and identified fourteen compounds that were subsequently tested in vitro against the MCF-7 human breast adenocarcinoma cell line. Eleven out of the fourteen compounds exhibited inhibitory activity with IC50 values ranging between 30 and 186 μM. The results of the study confirmed the fundamental validity of the chosen approach as a hit discovery tool.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, I-53100 Siena, Italy; European Research Centre for Drug Discovery and Development (NatSynDrugs), I-53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Panagiota
authors.initials: P
authors.lastname: Papazafiri
authors.forename: Vassilios
authors.initials: V
authors.lastname: Roussis
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents
keywords: 3D-QSAR; Antiestrogenic activity; MCF-7; Pharmacophore modeling; SERM; Virtual screening