This work demonstrates an effective combination of computational analysis and simple bacterial screens for rapid identification of potential hormone-like therapeutics.

BACKGROUND: Estrogenic activity has been observed in several industrial and household products, and some evidence suggests that this activity may be linked to increased pathologies in humans and animals. Here, an engineered strain of Escherichia coli is evaluated for its ability to detect estrogenic activity in complex mixtures, including natural dietary supplements, hand and body washes, essential oils, and perfumes. The engineered E. coli biosensor strain expresses the ligand-binding domain of the human estrogen receptor β (ERβ) as part of a larger allosteric reporter enzyme. The result is a simple bacterial growth assay, where estrogenic activity of a test compound is reflected by increased cell growth on a simple defined medium.

Increasing attention is being paid to the role of selenium, both as an essential component required for the activity of many enzymes and in the context of selenium-based pharmaceutical agents. A wide range of therapeutics that include selenium are on the market and under development, such as antihypertensive, anticancerogenic, antiviral, and immunosuppressive agents. Computer-aided drug design (CADD) has proven to be an important tool for the development of new drugs. Many CADD techniques, including docking, molecular dynamics simulation, and other receptor-based approaches, require an accurate understanding of the nature of the intermolecular forces that act to stabilize protein-ligand complexes; moreover, a quantitative assessment of these interactions furthers our efforts to rationalize the drug design process. In this paper, we consider one class of interaction involving selenium, that between Se and aromatic rings. Prior work has shown that interactions between divalent sulfur and aromatic rings are observed much more frequently than would be expected on the basis of chance, both in protein structures and the crystal structures of organic compounds that include these moieties. Recent studies on the optimization of inhibitor-protein binding also suggest that sulfur-aromatic interactions are important in stabilizing these complexes and may be crucial focal point for CADD. Given that selenium and sulfur have similar chemistry, and that selenium is significantly more polarizable, we propose that Se-aromatic interactions may also play an important stabilizing role in the structure of folded proteins and in drug-protein complexes. We have tested this hypothesis against data from the Cambridge Crystallographic Database and ab initio quantum chemical calculations. We have found evidence that selenium does interact strongly with aromatic rings and may play a role analogous to sulfur in stabilizing protein folds. In addition, selenium should be considered along with sulfur in rational drug design strategies that seek to improve binding to target protein sites that include aromatic rings.