Computational Insights into the Diabetogenic Potential of 4-Nonylphenol Via Estrogen and Insulin Signaling Interference
Sandhya Sharma
Department of Zoology, MMV, Banaras Hindu University, Varanasi, India.
Shubhanshi Kulshrestha
Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi, India.
Gautam Geeta J. *
Department of Zoology, MMV, Banaras Hindu University, Varanasi, India.
*Author to whom correspondence should be addressed.
Abstract
Background: Endocrine disrupting chemicals (EDCs) are present in daily use products such as detergents, personal care products and plastics. These EDCs are associated with different metabolic and endocrine disorders. 4-Nonylphenol is a byproduct produced after the breakdown of alkylphenol ethoxylates. 4-NP shows estrogenic action and persists in the environment for a long time. There is possibility of interference in glucose homeostasis and involvement in developing Type Diabetes Mellitus (T2DM) by interfering with the signalling pathways related to estrogen and insulin.
Objective: In the present study molecular interaction between 4-NP and target proteins related to estrogen and insulin signaling to understand its possible role in metabolic disorders such as T2DM.
Methods: The present study used an in-silico molecular docking bioinformatic tool to predict the molecular interaction between 4-NP and nine target proteins related to estrogen and insulin signalling pathways. Nine target proteins were selected: ESR1, ESR2, GPER, INSR, IRS1, IRS2, PI3K, AKT, and GLUT-4 and binding affinities were determined by using AlphaFold, AutoDock Vina, and Maestro. Furthermore, AlphaFold and LigPlot were used to determine hydrogen bonds and hydrophobic interactions.
Results: The docking analysis showed that the binding affinity of the ligand ranged from -6.2 to -9.1 kcal/mol. The strongest binding has been observed for PI3K and GLUT-4, indicating that the ligand might interfere with insulin-induced glucose uptake. The presence of stable complexes was confirmed by the presence of 1-3 hydrogen bonds and hydrophobic interactions. The binding of the ligand to ESR1, ESR2, and GPER (binding affinity of around -7.5 to -8.0 kcal/mol) also indicated that the ligand might modulate the function of estrogen receptors and the role of β cells in the pancreas.
Conclusions: The study suggests that the ligand 4-NP might strongly interact with target proteins that play important roles in the regulation of estrogen and insulin signalling.
Keywords: 4-Nonylphenol, endocrine-disrupting chemicals, estrogen receptors, molecular docking, type 2 diabetes mellitus