title: Biotransformation and molecular docking studies of aromatase inhibitors.
abstract: Bioconversion of the aromatase inhibitor formestane (4-hydroxyandrost-4-ene-3,17-dione) (1) by the fungus Rhizopus oryzae ATCC 11145 resulted in a new minor metabolite 3,5α-dihydroxyandrost-2-ene-4,17-dione (2) and the known 4β,5α-dihydroxyandrostane-4,17-dione (3) as the major product. The structural elucidation and bioactivities of these metabolites are reported herein. Molecular modeling studies of the interactions between these metabolites and the aromatase protein indicated that acidic (D309), basic (R115), polar (T310), aromatic (F134, F221, and W224), and non-polar (I133, I305, A306, V369, V370, L372, V373, M374, and L477) amino acid residues contribute important interactions with the steroidal substrates. These combined experimental and theoretical studies provide fresh insights for the further development of more potent aromatase inhibitors.
authors.affiliation: Department of Life and Physical Sciences, Fisk University, 1000 17th Ave N, Nashville, TN 37208, United States. Electronic address: gmartin@fisk.edu.
authors.forename: Glenroy D A
authors.initials: GD
authors.lastname: Martin
authors.affiliation: Chemistry, Biochemistry and Physics Department, The University of Tampa, 401 West Kennedy Blvd., Tampa, FL 33606, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: Narvaez
authors.affiliation: Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bulmer
authors.affiliation: Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom. Electronic address: marcus.durrant@northumbria.ac.uk.
authors.forename: Marcus C
authors.initials: MC
authors.lastname: Durrant
mesh_terms: D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001711:Biotransformation; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012233:Rhizopus / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors
keywords: Aromatase inhibitor; Biotransformation; Cytochrome P450 monooxygenase; Formestane; Molecular docking; Rhizopus oryzae