A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

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.

LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation

“…Accordingly, tamoxifen docked with its cationic tertiary amino group remote to the Arg103 side-chains (Figures 1l and Supplementary Figure 1); these side-chains instead formed cation- interactions with the phenyl group of tamoxifen ( Figure 1l). The interaction of the tamoxifen pose was computed as having a calculated ligand-binding affinity of -6.5 kcal mol -1 via the molecular mechanics/generalized Born volume integration (MM/GBVI) method (15,16). The binding energies of the anionic ligands were also predicted as favourable, ranging from -5.1 (DCPIB) to -5.8 kcal mol -1 (MONNA).…”

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism

“…Molecular docking is a valid computational approach to test the potential for ligand binding in silico before moving on to more resource-consuming experimental methodologies (55,56). …”

Towards a non-animal risk assessment for anti-androgenic effects in humans

“…Simplicity is also a limitation, in that this type of QSAR approach does not attempt to describe the subtleties of the ligand-receptor interaction such as binding kinetics and flexibility of the receptor or ligand (Hovarth et al, 2005). Understanding the nature of the ligand-receptor interaction is critical, since low affinity ligands are much less likely to exert biological effects due to the limited time spent in the receptor binding site (Galli et al, 2014). Some of these limitations can be overcome by developing models for which the starting point is not the ligand but the receptor.…”

“…If the chosen tool deems an interaction is plausible, a validated AR binding study is available to test the ability of the radiolabelled test chemical to competitively bind ARs from the homogenized prostate of castrated rats (EPA, 2009). Although model protocols have been developed using recombinant AR which negates the requirement for animal tissue (Freyberger et al, 2010a), differences in the ligand binding domain between the human and rat AR (Galli et al, 2014) indicate that a human-based system would be preferable. Receptor binding studies cannot indicate whether a chemical will act as an agonist or an antagonist, and can therefore not provide dose-response data needed for a safety assessment.…”