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A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Galli CL, Sensi C, Fumagalli A, Parravicini C, Marinovich M, Eberini I - PLoS ONE (2014)

Bottom Line: We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking.Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three).The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italia.

ABSTRACT
Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

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Related in: MedlinePlus

Hazard evaluation pipeline for putative androgen disruptors.Step 1: database production; step 2: in silico binding assay; step 3 in vitro binding assay for the selected dataset; step 4: in vitro activity assays only for the high affinity molecules (positive hits); and identification of agonist (α = 1), partial agonist (1<α<0) and antagonist (α = 0) activity.
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pone-0104822-g007: Hazard evaluation pipeline for putative androgen disruptors.Step 1: database production; step 2: in silico binding assay; step 3 in vitro binding assay for the selected dataset; step 4: in vitro activity assays only for the high affinity molecules (positive hits); and identification of agonist (α = 1), partial agonist (1<α<0) and antagonist (α = 0) activity.

Mentions: While the in silico screening cannot be used as a stand-alone procedure, it can be successfully used as a first prioritizing step in a tier approach (Figure 7). The second mandatory check for the in silico positive hits should be an in vitro evaluation procedure, in which the affinity of the positive hits are measured through a reference cellular assay. From our results, the choice of the species to use in competitive binding assay should be carried out carefully, because it may lead to hazard over-under-estimation.


A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Galli CL, Sensi C, Fumagalli A, Parravicini C, Marinovich M, Eberini I - PLoS ONE (2014)

Hazard evaluation pipeline for putative androgen disruptors.Step 1: database production; step 2: in silico binding assay; step 3 in vitro binding assay for the selected dataset; step 4: in vitro activity assays only for the high affinity molecules (positive hits); and identification of agonist (α = 1), partial agonist (1<α<0) and antagonist (α = 0) activity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128724&req=5

pone-0104822-g007: Hazard evaluation pipeline for putative androgen disruptors.Step 1: database production; step 2: in silico binding assay; step 3 in vitro binding assay for the selected dataset; step 4: in vitro activity assays only for the high affinity molecules (positive hits); and identification of agonist (α = 1), partial agonist (1<α<0) and antagonist (α = 0) activity.
Mentions: While the in silico screening cannot be used as a stand-alone procedure, it can be successfully used as a first prioritizing step in a tier approach (Figure 7). The second mandatory check for the in silico positive hits should be an in vitro evaluation procedure, in which the affinity of the positive hits are measured through a reference cellular assay. From our results, the choice of the species to use in competitive binding assay should be carried out carefully, because it may lead to hazard over-under-estimation.

Bottom Line: We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking.Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three).The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italia.

ABSTRACT
Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

Show MeSH
Related in: MedlinePlus