PUBLICATION
In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin
- Authors
- Thorsteinson, N., Ban, F., Santos-Filho, O., Tabaei, S.M., Miguel-Queralt, S., Underhill, C., Cherkasov, A., and Hammond, G.L.
- ID
- ZDB-PUB-080902-8
- Date
- 2009
- Source
- Toxicology and applied pharmacology 234(1): 47-57 (Journal)
- Registered Authors
- Hammond, Geoff
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding, Competitive
- Computational Biology/methods*
- Computer Simulation*
- Databases, Factual
- Dihydrotestosterone/metabolism
- Drug Discovery/methods
- Ligands
- Models, Molecular
- Protein Binding
- Quantitative Structure-Activity Relationship*
- Sequence Homology
- Sex Hormone-Binding Globulin/metabolism*
- Xenobiotics/administration & dosage
- Xenobiotics/chemistry
- Xenobiotics/metabolism*
- Zebrafish/physiology
- PubMed
- 18725242 Full text @ Tox. App. Pharmacol.
- CTD
- 18725242
Citation
Thorsteinson, N., Ban, F., Santos-Filho, O., Tabaei, S.M., Miguel-Queralt, S., Underhill, C., Cherkasov, A., and Hammond, G.L. (2009) In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin. Toxicology and applied pharmacology. 234(1):47-57.
Abstract
Anthropogenic compounds with the capacity to interact with the steroid-binding site of sex hormone binding globulin (SHBG) pose health risks to humans and other vertebrates including fish. Building on studies of human SHBG, we have applied in silico drug discovery methods to identify potential binders for SHBG in zebrafish (Danio rerio) as a model aquatic organism. Computational methods, including; homology modeling, molecular dynamics simulations, virtual screening, and 3D QSAR analysis, successfully identified 6 non-steroidal substances from the ZINC chemical database that bind to zebrafish SHBG (zfSHBG) with low-micromolar to nanomolar affinities, as determined by a competitive ligand-binding assay. We also screened 80,000 commercial substances listed by the European Chemicals Bureau and Environment Canada, and 6 non-steroidal hits from this in silico screen were tested experimentally for zfSHBG binding. All 6 of these compounds displaced the [(3)H]5alpha-dihydrotestosterone used as labeled ligand in the zfSHBG screening assay when tested at a 33 muM concentration, and 3 of them (hexestrol, 4-tert-octylcatechol, and dihydrobenzo(a)pyren-7(8H)-one) bind to zfSHBG in the micromolar range. The study demonstrates the feasibility of large-scale in silico screening of anthropogenic compounds that may disrupt or highjack functionally important protein:ligand interactions. Such studies could increase the awareness of hazards posed by existing commercial chemicals at relatively low cost.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping