Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin

• Published in: Scientific reports Vol. 9; no. 1; p. 6810
• Main Authors: Chitrala, Kumaraswamy Naidu, Yang, Xiaoming, Busbee, Brandon, Singh, Narendra P., Bonati, Laura, Xing, Yongna, Nagarkatti, Prakash, Nagarkatti, Mitzi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.05.2019; Nature Publishing Group
• Subjects: 101/47; 631/114; 631/250; Amino Acids; Angiogenesis; Animals; Binding Sites; Computational Biology; Computer applications; Contaminants; Dioxins; DNA-binding protein; Helix-loop-helix proteins (basic); Humanities and Social Sciences; Humans; Ligands; Mice; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; multidisciplinary; Phosphorylation; Polychlorinated Dibenzodioxins - chemistry; Polychlorinated Dibenzodioxins - pharmacology; Protein Binding; Quantitative Structure-Activity Relationship; Reproducibility of Results; Science; Science (multidisciplinary); TCDD; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-1 - chemistry
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43232-4

The toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, primarily depend on its ability to activate aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor belonging to the superfamily of basic-helix-loop-helix DNA-binding proteins. In the present study, we aimed to identify novel protein receptor targets for TCDD using computational and in vitro validation experiments. Interestingly, results from computational methods predicted that Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) could be one of the potential targets for TCDD in both mouse and humans. Results from molecular docking studies showed that human VEGFR1 (hVEGFR1) has less affinity towards TCDD compared to the mouse VEGFR1 (mVEGFR1). In vitro validation results showed that TCDD can bind and phosphorylate hVEGFR1. Further, results from molecular dynamic simulation studies showed that hVEGFR1 interaction with TCDD is stable throughout the simulation time. Overall, the present study has identified VEGFR1 as a novel target for TCDD, which provides the basis for further elucidating the role of TCDD in angiogenesis.