In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin

Toxicology and Applied Pharmacology
Nels ThorsteinsonGeoffrey L Hammond

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 microM 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 feasibil...Continue Reading

References

Aug 1, 1996·Journal of Computer-aided Molecular Design·G M MorrisA J Olson
Feb 7, 1997·The Journal of Biological Chemistry·E J Routledge, J P Sumpter
Apr 8, 2000·Bulletin of Environmental Contamination and Toxicology·S DongH Yu
Feb 28, 2001·The Journal of Steroid Biochemistry and Molecular Biology·H Hodgert JuryG L Hammond
Mar 30, 2001·Journal of Chemical Information and Computer Sciences·S S LiuS X Cai
Jun 11, 2002·Journal of Molecular Biology·Irina GrishkovskayaYves A Muller
Jun 28, 2002·Journal of Chemical Information and Computer Sciences·Kari TuppurainenMikael Peräkylä
Jun 28, 2002·Journal of Chemical Information and Computer Sciences·Shu-Shen LiuLian-Sheng Wang
Aug 29, 2003·The Journal of Steroid Biochemistry and Molecular Biology·Geoffrey L HammondYves A Muller
Oct 17, 2003·Photochemical & Photobiological Sciences : Official Journal of the European Photochemistry Association and the European Society for Photobiology·Patrick Mazellier, Julie Leverd
Nov 25, 2003·Journal of Chemical Information and Computer Sciences·Samuli-Petrus KorhonenMikael Peräkylä
Apr 29, 2004·SAR and QSAR in Environmental Research·A H AsikainenK A Tuppurainen
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Jul 31, 2004·Endocrinology·Solange Miguel-QueraltGeoffrey L Hammond
Jan 26, 2005·Journal of Chemical Information and Modeling·John J Irwin, Brian K Shoichet
Mar 8, 2005·Birth Defects Research. Part A, Clinical and Molecular Teratology·Frederick S Vom SaalWade V Welshons
Apr 29, 2005·Journal of Medicinal Chemistry·Artem CherkasovGeoffrey L Hammond
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Jul 25, 2006·Journal of Molecular Graphics & Modelling·Zsolt ZsoldosA Peter Johnson
Aug 21, 2007·Reproductive Toxicology·Ruth A KeriGail S Prins
Aug 28, 2007·Molecular and Cellular Endocrinology·Solange Miguel-QueraltGeoffrey L Hammond
Aug 1, 1988·Journal of the American Chemical Society·R D CramerJ D Bunce

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Citations

Nov 28, 2009·Journal of Computer-aided Molecular Design·Asmund RinnanSøren Balling Engelsen
Apr 24, 2012·Toxicology and Applied Pharmacology·Angelo VedaniMartin Smieško
Sep 24, 2009·Molecular and Cellular Endocrinology·Julien BobeAlexis Fostier
Sep 15, 2009·Molecular and Cellular Endocrinology·George V AvvakumovGeoffrey L Hammond
Sep 30, 2009·Molecular and Cellular Endocrinology·Michel PugeatCatherine Grenot
May 31, 2014·SAR and QSAR in Environmental Research·A K SaxenaS Ahmed
Jan 12, 2019·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Sugunadevi SakkiahHuixiao Hong
May 22, 2019·Frontiers in Neuroendocrinology·Matthieu KellerThierry D Charlier

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