title: Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors.
abstract: Suppression of estrogen biosynthesis by aromatase inhibition is an effective approach for the treatment of hormone sensitive breast cancer. Third generation non-steroid aromatase inhibitors have shown important benefits in recent clinical trials with postmenopausal women. In this study we have developed a new ligand-based strategy combining important pharmacophoric and structural features according to the postulated aromatase binding mode, useful for the virtual screening of new potent non-steroid inhibitors. A small subset of promising drug candidates was identified from the large NCI database, and their antiaromatase activity was assessed on an in vitro biochemical assay with aromatase extracted from human term placenta. New potent aromatase inhibitors were discovered to be active in the low nanomolar range, and a common binding mode was proposed. These results confirm the potential of our methodology for a fast in silico high-throughput screening of potent non-steroid aromatase inhibitors.
authors.affiliation: Faculdade de Farmacia, Laboratorio de Quimica Farmaceutica, Centro de Estudos Farmaceuticos, Universidade de Coimbra, 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: D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D006801:Humans; D021621:Imaging, Three-Dimensional; D000077289:Letrozole; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D013256:Steroids / Q000737:chemistry; D013329:Structure-Activity Relationship; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D013256:Steroids; D014230:Triazoles; D000077289:Letrozole