CERAPP: Collaborative Estrogen Receptor Activity Prediction Project
Background: Humans are exposed to thousands of man-made chemicals in the environment.
Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine
disruptors. Most of these chemicals have never been tested for their ability to interact with the
estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly
in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program.
Objectives: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen
Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational
models trained on high-throughput screening data to evaluate thousands of chemicals for
ER-related activity and prioritize them for further testing.
Methods: CERAPP combined multiple models developed in collaboration with 17 groups in the
United States and Europe to predict ER activity of a common set of 32,464 chemical structures.
Quantitative structure–activity relationship models and docking approaches were employed, mostly
using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of
40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions
were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of
single models, a consensus was built by weighting models on scores based on their evaluated accuracies.
Results: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities.
Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high
priority actives and 6,742 potential actives (20.8%) to be considered for further testing.
Conclusion: This project demonstrated the possibility to screen large libraries of chemicals using a
consensus of different in silico approaches. This concept will be applied in future projects related to
other end points.
MANSOURI Kamel;
ABDELAZIZ Ahmed;
RYBACKA Aleksandra;
RONCAGLIONI Alessandra;
TROPSHA Alexander;
VARNEK Alexandre;
ZAKHAROV Alexey;
WORTH Andrew;
RICHARD Ann;
GRULKE Christopher;
TRISCIUZZI Daniela;
FOURCHES Denis;
HORVATH Dragos;
BENFENATI Emilio;
MURATOV Eugene;
EVA Wedebye;
GRISONI Francesca;
MANGIATORDI Giuseppe;
INCISIVO Giuseppina;
HONG Huixiao;
NG Hui;
TETKO Igor;
BALABIN Ilya;
KANCHERLA Jayaram;
SHEN Jie;
BURTON Julien;
NICKLAUS Marc;
CASSOTTI Matteo;
NIKOLOV Nikolai;
NICOLOTTI Orazio;
ANDERSSON Patrik;
ZANG Qingda;
POLITI Regina;
BEGER Richard D.;
TODESCHINI Roberto;
HUANG Ruili;
FARAG Sherif;
ROSENBERG Sine;
SLAVOV Svetoslav;
HU Xin;
JUDSON Richard;
2016-10-28
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
JRC95481
0091-6765,
http://ehp.niehs.nih.gov/15-10267/,
https://publications.jrc.ec.europa.eu/repository/handle/JRC95481,
10.1289/ehp.1510267,
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