title: An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors.
abstract: Aromatase, an enzyme involved in the conversion of androgens into estrogens, is an important target for the endocrine treatment of breast cancer. Aromatase inhibition is usually achieved with steroids structurally related to the substrate of catalysis or, alternatively, with azole non-steroid compounds. Substituted androstenedione derivatives with Delta(1), Delta(6) and Delta(1,6) unsaturations and 6-alkyl/6-phenyl aliphatic substitutions, are among the most potent steroid aromatase inhibitors known to date. In this paper we have combined the common pharmacophoric and shape features of these molecules into a new pharmacophore model, useful for virtual screening of large compound databases. Small subsets of the best fitting anti-aromatase candidates were extracted from the NCI database and experimentally tested on an in vitro assay with human placental aromatase. New potent aromatase inhibitors were identified such as compounds 8 and 14. Considering the lack of a crystal structure for the aromatase enzyme, this ligand-based method is a valuable tool for the virtual screening of new aromatase inhibitors.
authors.affiliation: Faculdade de Farmácia, Centro de Estudos Farmacêuticos, Lab Química Farmacêutica, Universidade de Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Marco A C
authors.initials: MA
authors.lastname: Neves
authors.forename: Teresa C P
authors.initials: TC
authors.lastname: Dinis
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Sá e Melo
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D006801:Humans; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013329:Structure-Activity Relationship
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D000735:Androstenedione; D001141:Aromatase