In silico study of molecular mechanisms of action: Oestrogenic disruptors among phthalate esters


Phthalate esters (PAEs), as widely used plasticisers, have been concerned for their possible disruption of oestrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in-silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the oestrogenic potencies of PAEs. The transcriptional activation functions of human ER? (hER?) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hER?, conformational changes of PAEs-hER? complexes and recruitment of coactivators. Molecular insight into the diverse oestrogen mechanism of action among PAEs with regard to hER? agonists and selective oestrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hER? leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hER?. Conversely, binding interaction of hER? with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hER? agonist or SERMs.

Authors: Zhu Q, Liu L, Zhou X, Ma M.
; Full Source: Environmental Pollution. 2019 Sep 7;255(Pt 1):113193. doi: 10.1016/j.envpol.2019.113193. [Epub ahead of print]