Discovery of New Protein Targets of BPA Analogs and Derivatives Associated with Noncommunicable Diseases: A Virtual High-Throughput Screening

Abstract

Background: Bisphenol A analogs and derivatives (BPs) have emerged as new contaminants with little or no information about their toxicity. These have been found in numerous everyday products, from thermal paper receipts to plastic containers, and measured in human samples. Objectives: The objectives of this research were to identify in silico new protein targets of BPs associated with seven noncommunicable diseases (NCDs), and to study their protein–ligand interactions using computer-aided tools. Methods: Fifty BPs were identified by a literature search and submitted to a virtual high-throughput screening (vHTS) with 328 proteins associated with NCDs. Protein–protein interactions between predicted targets were examined using STRING, and the protocol was validated in terms of binding site recognition and correlation between in silico affinities and in vitro data. Results: According to the vHTS, several BPs may target proteins associated with NCDs, some of them with stronger affinities than bisphenol A (BPA). The best affinity score (the highest in silico affinity absolute value) was obtained after docking 4,4′-bis( N -carbamoyl-4-methylbenzensulfonamide)diphenylmethane (BTUM) on estradiol 17-beta-dehydrogenase 1 ( ). However, other molecules, such as bisphenol A bis(diphenyl phosphate) (BDP), bisphenol PH (BPPH), and Pergafast 201 also exhibited great affinities (top 10 affinity scores for each disease) with proteins related to NCDs. Discussion: Molecules such as BTUM, BDP, BPPH, and Pergafast 201 could be targeting key signaling pathways related to NCDs. These BPs should be prioritized for in vitro and in vivo toxicity testing and to further assess their possible role in the development of these diseases. https://doi.org/10.1289/EHP7466

Azole-Induced Color Vision Deficiency Associated with Thyroid Hormone Signaling: An Integrated In Vivo, In Vitro, and In Silico Study

“…Many in silico methods, such as molecular docking, have been developed to study the interaction of xenobiotics with target receptors and to be a first step in determining the toxicological mode of action. ,− , Before investigating the interaction between azoles and TR isoforms, we used T3 as a positive control due to its known potent TR agonistic capacity . T3-TRα LBD and T3-TRβ LBD complexes produced low RMSD values (<1.2 Å), demonstrating good predictability of our docking protocol for identification of the binding site and ligand pose compared with the corresponding crystallographic structures. , Based on the lowest affinity score obtained by the blind molecular docking analysis, , CBZ and TDF preferred to occupy the binding pocket where T3, the native ligand for TR isoforms, was located (Figure S6). A strong binding affinity of CBZ and TDF to TR isoforms was observed in the binding pocket through hydrogen bonds (Figure ).…”

“…17 T3-TRα LBD and T3-TRβ LBD complexes produced low RMSD values (<1.2 Å), demonstrating good predictability of our docking protocol for identification of the binding site and ligand pose compared with the corresponding crystallographic structures. 30,57 Based on the lowest affinity score obtained by the blind molecular docking analysis, 30,31 CBZ and TDF preferred to occupy the binding pocket where T3, the native ligand for TR isoforms, was located (Figure S6). A strong binding affinity of CBZ and TDF to TR isoforms was observed in the binding pocket through hydrogen bonds (Figure 4).…”