TY - JOUR
T1 - Biotransformation and molecular docking studies of aromatase inhibitors
AU - Martin, Glenroy
AU - Narvaez, Javier
AU - Bulmer, Rachel
AU - Durrant, Marcus
N1 - Funding information: This work was partly funded by a grant provided by the National High Magnetic Field Laboratory (NHMFL) user grant (ML-Martin-002), the American Chemical Society (ACS) Project SEED endowment, the Hillsborough County Public Schools Academic Programs, and the ACS Tampa Bay local section. We thank Professor John Pezzuto, Eun-Jung Park and Tamara Kondratyuk (University of Hawaii at Hilo) for conducting aromatase and cytotoxic assays. We are grateful to James Rocca (NHFML) for conducting 1D and 2D NMR experiments.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Bioconversion of the aromatase inhibitor formestane (4-hydroxyandrost-4-ene-3,17-dione) by the fungus Rhizopus oryzae ATCC 11145 resulted in a new minor metabolite 3,5α-dihydroxyandrost-2-ene-4,17-dione and the known 4β,5α-dihydroxyandrostane-4,17-dione 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.
AB - Bioconversion of the aromatase inhibitor formestane (4-hydroxyandrost-4-ene-3,17-dione) by the fungus Rhizopus oryzae ATCC 11145 resulted in a new minor metabolite 3,5α-dihydroxyandrost-2-ene-4,17-dione and the known 4β,5α-dihydroxyandrostane-4,17-dione 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.
KW - Aromatase inhibitor
KW - Molecular docking
KW - Rhizopus oryzae
KW - Formestane
KW - Biotransformation
KW - Cytochrome P450 monooxygenase
UR - https://www.scopus.com/pages/publications/84978718896
U2 - 10.1016/j.steroids.2016.07.003
DO - 10.1016/j.steroids.2016.07.003
M3 - Article
SN - 0039-128X
VL - 113
SP - 95
EP - 102
JO - Steroids
JF - Steroids
ER -
