Urban Endocrine Disruptors Targeting Breast Cancer Proteins
Barnardes, Gonçalo JL
Olivero-Verbel, Jesus Tadeo
Chemical Research in Toxicology
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Montes-Grajales, D., Barnardes, G. J., & Olivero-Verbel, J. T. (2015). Urban Endocrine Disruptors Targeting Breast Cancer Proteins. Chemical Research in Toxicology, 29 150-161. https://doi.org/10.1021/acs.chemrestox.5b00342
Humans are exposed to a huge amount of environmental pollutants called endocrine disrupting chemicals (EDCs). These molecules interfere with the homeostasis of the body, usually through mimicking natural hormones leading to activation or blocking their receptors. Many of these compounds have been associated to a broad range of diseases including the development or increased susceptibility to breast cancer, the most prevalent cancer in woman worldwide, according to the World Health Organization. Thus, this article presents a virtual high-throughput screening (vHTS) to evaluate the affinity of proteins related to breast cancer, such as ESR1, ERBB2, PGR, BCRA1 and SHBG, among others, with EDCs from urban sources. A blind docking strategy was employed to screen each protein-ligand pair by triplicate in AutoDock Vina 2.0, using the computed binding affinities as ranking criteria. The three-dimensional structures were previously obtained from EDCs DataBank and Protein Data Bank, prepared and optimized by SYBYL X-2.0. Some of the chemicals that exhibited the best affinity scores for breast cancer proteins in each category were 1,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A derivatives, perfluorooctane sulfonic acid and benzo(a)pyrene, for catalase, several proteins, sex hormone-binding globulin and cytochrome P450 1A2, respectively. An experimental validation of this approach was performed with a complex that gave a moderate binding affinity in silico, the sex hormone binding globulin (SHBG) and bisphenol A (BPA) complex. The protein was obtained using DNA recombinant technology and the physical interaction with BPA assessed through spectroscopic techniques. BPA binds on the recombinant SHBG, and this results in an increase of its alpha helix content. In short, this work shows the potential of several EDCs to bind breast cancer associated proteins, as a tool to prioritize compounds to perform in vitro analysis to benefit the regulation or exposure prevention by the general population.
Endocrine disrupting chemical, BPA, breast cancer, circular dichroism, highthroughput virtual screening
This work was supported by Colciencias (567-2012 to D.M-G., 1107-519-29058, 1107-459- 21616), the University of Cartagena (0342010) and the EPSRC. G.J.L.B. is a Royal Society University Research Fellow.
European Commission (EC) (852985)
External DOI: https://doi.org/10.1021/acs.chemrestox.5b00342
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253117