title: CERAPP: Collaborative Estrogen Receptor Activity Prediction Project.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 K, Abdelaziz A, Rybacka A, Roncaglioni A, Tropsha A, Varnek A, Zakharov A, Worth A, Richard AM, Grulke CM, Trisciuzzi D, Fourches D, Horvath D, Benfenati E, Muratov E, Wedebye EB, Grisoni F, Mangiatordi GF, Incisivo GM, Hong H, Ng HW, Tetko IV, Balabin I, Kancherla J, Shen J, Burton J, Nicklaus M, Cassotti M, Nikolov NG, Nicolotti O, Andersson PL, Zang Q, Politi R, Beger RD, Todeschini R, Huang R, Farag S, Rosenberg SA, Slavov S, Hu X, Judson RS. 2016.
  
  
  
  Collaborative Estrogen Receptor Activity Prediction Project. Environ Health Perspect 124:1023-1033; http://dx.doi.org/10.1289/ehp.1510267.
authors.affiliation: National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mansouri
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelaziz
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rybacka
authors.forename: Alessandra
authors.initials: A
authors.lastname: Roncaglioni
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
authors.forename: Alexandre
authors.initials: A
authors.lastname: Varnek
authors.forename: Alexey
authors.initials: A
authors.lastname: Zakharov
authors.forename: Andrew
authors.initials: A
authors.lastname: Worth
authors.forename: Ann M
authors.initials: AM
authors.lastname: Richard
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grulke
authors.forename: Daniela
authors.initials: D
authors.lastname: Trisciuzzi
authors.forename: Denis
authors.initials: D
authors.lastname: Fourches
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.forename: Emilio
authors.initials: E
authors.lastname: Benfenati
authors.forename: Eugene
authors.initials: E
authors.lastname: Muratov
authors.forename: Eva Bay
authors.initials: EB
authors.lastname: Wedebye
authors.forename: Francesca
authors.initials: F
authors.lastname: Grisoni
authors.forename: Giuseppe F
authors.initials: GF
authors.lastname: Mangiatordi
authors.forename: Giuseppina M
authors.initials: GM
authors.lastname: Incisivo
authors.forename: Huixiao
authors.initials: H
authors.lastname: Hong
authors.forename: Hui W
authors.initials: HW
authors.lastname: Ng
authors.forename: Igor V
authors.initials: IV
authors.lastname: Tetko
authors.forename: Ilya
authors.initials: I
authors.lastname: Balabin
authors.forename: Jayaram
authors.initials: J
authors.lastname: Kancherla
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Julien
authors.initials: J
authors.lastname: Burton
authors.forename: Marc
authors.initials: M
authors.lastname: Nicklaus
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassotti
authors.forename: Nikolai G
authors.initials: NG
authors.lastname: Nikolov
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
authors.forename: Qingda
authors.initials: Q
authors.lastname: Zang
authors.forename: Regina
authors.initials: R
authors.lastname: Politi
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.forename: Roberto
authors.initials: R
authors.lastname: Todeschini
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Sherif
authors.initials: S
authors.lastname: Farag
authors.forename: Sine A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Slavov
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
mesh_terms: D003198:Computer Simulation; D052244:Endocrine Disruptors / Q000145:classification / Q000633:toxicity*; D058735:Environmental Policy; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000378:metabolism*; D018675:Toxicity Tests; D014481:United States
chemical_list: D052244:Endocrine Disruptors; D011960:Receptors, Estrogen