TY  - JOUR
A1  - Rakers, Christin
A1  - Schumacher, Fabian
A1  - Meinl, Walter
A1  - Glatt, Hansruedi
A1  - Kleuser, Burkhard
A1  - Wolber, Gerhard
T1  - In Silico Prediction of Human Sulfotransferase 1E1 Activity Guided by Pharmacophores from Molecular Dynamics Simulations
JF  - The journal of biological chemistry
N2  - Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model, and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28% of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.
KW  - drug design
KW  - drug metabolism
KW  - liver metabolism
KW  - molecular dynamics
KW  - molecular modeling
KW  - sulfotransferase
Y1  - 2016
U6  - https://doi.org/10.1074/jbc.M115.685610
SN  - 0021-9258
SN  - 1083-351X
VL  - 291
SP  - 58
EP  - 71
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  -