Predicting estrogen receptor binding of chemicals using a suite of in silico methods – Complementary approaches of (Q)SAR, molecular docking and molecular dynamics
Cotterill, J.V. ; Palazzolo, L. ; Ridgway, C. ; Price, N. ; Rorije, E. ; Moretto, A. ; Peijnenburg, A. ; Eberini, I. - \ 2019
Toxicology and Applied Pharmacology 378 (2019). - ISSN 0041-008X
Estrogen receptor - In Silico - Low-mode molecular dynamics simulation - Molecular docking - QSAR
With the aim of obtaining reliable estimates of Estrogen Receptor (ER) binding for diverse classes of compounds, a weight of evidence approach using estimates from a suite of in silico models was assessed. The predictivity of a simple Majority Consensus of (Q)SAR models was assessed using a test set of compounds with experimental Relative Binding Affinity (RBA) data. Molecular docking was also carried out and the binding energies of these compounds to the ERα receptor were determined. For a few selected compounds, including a known full agonist and antagonist, the intrinsic activity was determined using low-mode molecular dynamics methods. Individual (Q)SAR model predictivity varied, as expected, with some models showing high sensitivity, others higher specificity. However, the Majority Consensus (Q)SAR prediction showed a high accuracy and reasonably balanced sensitivity and specificity. Molecular docking provided quantitative information on strength of binding to the ERα receptor. For the 50 highest binding affinity compounds with positive RBA experimental values, just 5 of them were predicted to be non-binders by the Majority QSAR Consensus. Furthermore, agonist-specific assay experimental values for these 5 compounds were negative, which indicates that they may be ER antagonists. We also showed different scenarios of combining (Q)SAR results with Molecular docking classification of ER binding based on cut-off values of binding energies, providing a rational combined strategy to maximize terms of toxicological interest.
In silico prioritization for endocrine active substances (EAS) and their in vitro validation
Eberini, I. ; Palazzolo, L. ; Peijnenburg, A.A.C.M. ; Guerrini, U. ; Parravicini, G. ; Moretto, A. ; Bovee, T.F.H. - \ 2016
Toxicology Letters 258 (2016)suppl.. - ISSN 0378-4274 - p. S120 - S120.
Comparison of NOEC values to EC10/EC20 values, including confidence intervals, in aquatic and terrestrial ecotoxicological risk assessment
Azimonti, G. ; Galimberti, F. ; Marchetto, F. ; Menaballi, L. ; Ullucci, S. ; Pellicioli, F. ; Caffi, A. ; Ceriani, L. ; Boer, W.J. de; Voet, H. van der; Moretto, A. - \ 2015
EFSA (EFSA Supporting Publications 12)
Testing of a cumulative and aggregate exposure model using biomonitoring studies and dietary records for Italian vineyard spray operators.
Kennedy, M.C. ; Glass, C.R. ; Fustinoni, S. ; Moretto, A. ; Mandic-Rajcevic, S. ; Riso, P. ; Turrini, A. ; Voet, H. van der; Hetmanski, M.T. ; Fussel, R.J. ; Klaveren, J.D. van - \ 2015
Food and Chemical Toxicology 79 (2015). - ISSN 0278-6915 - p. 45 - 53.
pesticide-residues - urinary concentrations - metabolites - food - tebuconazole - health
The need for improved tools to estimate the cumulative and aggregate exposure to compounds such as plant protection products (PPPs) is recognised in the EU Regulation 1107/2009. A new model has been developed to estimate the exposure within a population to single compounds or compounds within a Cumulative Action Group, considering dietary and non-dietary sources and multiple exposure routes. To test the model a field study was carried out in Italy with operators applying tebuconazole fungicides, with measurements of dermal exposure collected. Whole urine samples were collected and analysed to provide values for the absorbed dose of tebuconazole, with duplicate diet samples collected and analysed as a measure of dietary exposures. The model provided predicted values of exposure for combined dietary and non-dietary routes of exposures which were compared to the measured absorbed dose values based on urinary analysis. The model outputs provided mean daily exposure values of 1.77 (±1.96) µg a.s./kg BW which are comparable to measured mean values from the biomonitoring field study of 1.73 (±1.31) µg a.s./kg BW. To supplement the limited measurement data available, comparisons against other models were also made and found to be comparable.
The ACROPOLIS project: Its aims, achievements, and way forward
Klaveren, J.D. van; Kennedy, M.C. ; Moretto, A. ; Verbeke, W. ; Voet, H. van der - \ 2015
Food and Chemical Toxicology 79 (2015). - ISSN 0278-6915 - p. 1 - 4.
dopaminergic pc12 cells - azole fungicides - insecticides