In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin.
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 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.
Thorsteinson
Nels
N
Prostate Centre at the Vancouver General Hospital, University of British Columbia, BC, Canada.
Ban
Fuqiang
F
Santos-Filho
Osvaldo
O
Tabaei
Seyed M H
SM
Miguel-Queralt
Solange
S
Underhill
Caroline
C
Cherkasov
Artem
A
Hammond
Geoffrey L
GL
D000818:Animals; D001667:Binding, Competitive; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D016208:Databases, Factual; D013196:Dihydrotestosterone / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D017385:Sequence Homology; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D015262:Xenobiotics / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D015027:Zebrafish / Q000502:physiology
D008024:Ligands; D012738:Sex Hormone-Binding Globulin; D015262:Xenobiotics; D013196:Dihydrotestosterone