Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells.

Abstract	Aromatase catalyses the conversion of androgens into estrogens and is a well-known target for breast cancer therapy. As it has been suggested that its activity is affected by inhibitors of phosphodiesterase-5, this work investigates the potential interaction of sildenafil with aromatase. This is carried out both at molecular level through structural and kinetics assays applied to the purified enzyme, and at cellular level using neuronal and breast cancer cell lines. Sildenafil is found to bind to aromatase with a KD of 0.58±0.05μM acting as a partial and mixed inhibitor with a maximal inhibition of 35±2%. Hyperfine sublevel correlation spectroscopy and docking studies show that sildenafil binds to the heme iron via its 6th axial water ligand. These results also provide information on the starting molecular scaffold for the development of new generations of drugs designed to inhibit aromatase as well as phosphodiesterase-5, a new emerging target for breast cancer therapy.
Authors	Roberta Baravalle, Francesca Valetti, Gianluca Catucci, Giovanna Gambarotta, Mario Chiesa, Sara Maurelli, Elio Giamello, Ines Barone, Stefania Catalano, Sebastiano Andò, Giovanna Di Nardo, Gianfranco Gilardi
Journal	The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 165 Issue Pt B Pg. 438-447 (01 2017) ISSN: 1879-1220 [Electronic] England
PMID	27616271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Chemical References	Aromatase Inhibitors Ligands Recombinant Proteins Water Heme Sildenafil Citrate Iron Aromatase CYP19A1 protein, human Cyclic Nucleotide Phosphodiesterases, Type 5
Topics	Aromatase (metabolism) Aromatase Inhibitors (chemistry) Breast Neoplasms (drug therapy, metabolism) Catalysis Cyclic Nucleotide Phosphodiesterases, Type 5 (metabolism) Dose-Response Relationship, Drug Electron Spin Resonance Spectroscopy Female Heme (chemistry) Humans Inhibitory Concentration 50 Iron (chemistry) Kinetics Ligands MCF-7 Cells Molecular Docking Simulation Protein Binding Recombinant Proteins (chemistry) Sildenafil Citrate (chemistry) Spectrophotometry Spectrophotometry, Ultraviolet Water (chemistry)

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