Bisphenol A or BPA is best-known substance in the bisphenol group. Its activity as endocrine disrupting chemical on the estrogen receptor alpha (ERα) is well researched and forms the basis of many regulatory restrictions on the use of BPA. In the plastics industry, consequently, the use of BPA analogues as BPA alternatives is increasing as they are not yet part of the regulatory limitations and their activity in the human body has not yet been clarified. Based on the structural similarities to BPA, analogues also have the potential for similar endocrine system toxicity.
In this master's thesis, we studied the binding of 38 selected BPA analogues to the ERα using virtual screening on pharmacophore models and molecular docking. In the LigandScout software, we prepared ligand-based and structure-based pharmacophore models and evaluated them by virtual screening with libraries containing active compounds and decoys on ERα. As expected, higher predictive value of the binding of the compounds investigated to ERα was obtained by structure-based pharmacophore models. Molecular docking was performed in the binding pockets of four Protein Data Bank crystal structures (3UU7, 3UUA, 3UUC, 3UUD) using the AutoDock Vina software. We examined the correlation among literature values on compound potency on ERα, in vitro values obtained at the Faculty of Pharmacy together with Pharmacophore-Fit score and affinity that represented the results of evaluation of pharmacophore modeling and molecular docking, respectively. These values do not indicate a good correlation, the assessment of the latter is difficult and unreliable due to the low range and lack of literature data on the potency of compounds.
In the second part of master's thesis, we used prepared pharmacophore models and molecular docking to analyze compounds related to plastics production. Information on compounds is collected from the article entitled: Overview of known plastic packaging-associated chemicals and their hazards. Both in silico methods, pharmacophore modeling and molecular docking showed comparable ability to identify bisphenols and compounds with similar structure. Most substances in the structural classes of bisphenols and related compounds are classified as endocrine disruptors according to the data collected in the article. We have classified all the compounds to which we have predicted potential activity on ERα using molecular docking and pharmacophore modeling and are not yet identified as hormone disruptors. We have prepared a list of compounds that are of interest for further research due to their potential to act as endocrine disrupting chemicals (EDC).
|
