Computational insights on agonist and antagonist mechanisms of estrogen receptor α induced by bisphenol A analogues. (May 2019)

• Record Type: Journal Article
• Authors: Cao, Huiming; Wang, Ling; Cao, Mengxi; Ye, Tong; Sun, Yuzhen
• Is Part Of: Environmental pollution. Volume 248(2019)
• Page Start: 536
• Page End: 545
• Publication Date: 2019-05
• Subjects: BPA analogues -- Anti-estrogenic activity -- Induce fit mechanism -- Antagonistic conformation -- Molecular dynamics simulations; Pollution -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmental Pollution -- Periodicals; Pollution -- Périodiques; Pollution -- Aspect de l'environnement -- Périodiques; Pollution -- Effets physiologiques -- Périodiques; Pollution; Pollution -- Environmental aspects; Periodicals; Electronic journals; 363.73
• DOI: 10.1016/j.envpol.2019.02.058
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: Structural analogues of bisphenol A (BPA) have become widely used as alternatives in BPA-free products. Most toxicological investigations have focused on the estrogenic activities of these analogues, which have been considered as potential environmental estrogens. However, recent studies revealed that certain BPA analogues could dramatically inhibit the proliferation of breast cancer cells, and exhibited strong anti-estrogenic effects compared with the antagonist 4-hydroxytamoxifen (OHT). Thus, we adopted computational models combining molecular dynamics simulations and binding free energy calculations to explore the underlying molecular basis of BPA analogues binding to estrogen receptor α (ERα). We also evaluated ligand-induced structural rearrangements of ERα at the atomic level. Conformational analyses showed that induced-fit H-bonding recognition by Thr347 was an important factor distinguishing antagonist from agonist BPA analogues. Moreover, antagonists of BPA analogues could indirectly induce the structural reposition of key helix 12 and produce an antagonistic conformation of ERα. Compared with OHT, the binding affinity of BPA analogues is stronger for antagonists than agonists. Taken together, we therefore propose computational indicators for screening of anti-estrogenic activities of BPA analogues, which may be beneficial for predicting the estrogenic or anti-estrogenic effects of BPA alternatives. Graphical abstract: Image 1 Highlights: Binding of BPA analogues elicits different conformations of Thr347. Indirect push mechanism of BPA analogues for ERα antagonistic conformation. Computational indicators were proposed to predict anti-estrogenic activities. Abstract : Novel antagonistic mechanism of estrogen receptor α was proposed to predict potential anti-estrogenic activities of BPA analogues.