Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00204-021-03111-2
Title: Structure-based virtual screening of CYP1A1 inhibitors: towards rapid tier-one assessment of potential developmental toxicants
Authors: Goh, Janice Jia Ni
Behn, Julian
Chong, Cheng-Shoong
Zhong, Guorui
Maurer-Stroh, Sebastian 
Fan, Hao 
Loo, Lit-Hsin 
Keywords: Allosteric
CYP1A1 inhibition
Developmental toxicity
Docking
Endocrine disruptors
Orthosteric
Issue Date: 28-Jun-2021
Publisher: Springer Science and Business Media Deutschland GmbH
Citation: Goh, Janice Jia Ni, Behn, Julian, Chong, Cheng-Shoong, Zhong, Guorui, Maurer-Stroh, Sebastian, Fan, Hao, Loo, Lit-Hsin (2021-06-28). Structure-based virtual screening of CYP1A1 inhibitors: towards rapid tier-one assessment of potential developmental toxicants. Archives of Toxicology 95 (9) : 3031-3048. ScholarBank@NUS Repository. https://doi.org/10.1007/s00204-021-03111-2
Rights: Attribution 4.0 International
Abstract: Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems. Here, we present a virtual screening model for CYP1A1 inhibitors based on the orthosteric and predicted allosteric sites of the enzyme. Using 1001 reference compounds with CYP1A1 activity data, we optimized the decision thresholds of our model and classified the training compounds with 68.3% balanced accuracy (91.0% sensitivity and 45.7% specificity). We applied our final model to 11 known CYP1A1 orthosteric binders and related compounds, and found that our ranking of the known orthosteric binders generally agrees with the relative activity of CYP1A1 in metabolizing these compounds. We also applied the model to 22 new test compounds with unknown/unclear CYP1A1 inhibitory activity, and predicted 16 of them are CYP1A1 inhibitors. The CYP1A1 potency and modes of inhibition of these 22 compounds were experimentally determined. We confirmed that most predicted inhibitors, including drugs contraindicated during pregnancy (amiodarone, bicalutamide, cyproterone acetate, ketoconazole, and tamoxifen) and environmental agents suspected to be endocrine disruptors (bisphenol A, diethyl and dibutyl phthalates, and zearalenone), are indeed potent inhibitors of CYP1A1. Our results suggest that virtual screening may be used as a rapid tier-one method to screen for potential CYP1A1 inhibitors, and flag them out for further experimental evaluations. © 2021, The Author(s).
Source Title: Archives of Toxicology
URI: https://scholarbank.nus.edu.sg/handle/10635/232591
ISSN: 0340-5761
DOI: 10.1007/s00204-021-03111-2
Rights: Attribution 4.0 International
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