Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway

Abstract

Glucocorticoids (GCs) are well known to exert broad-based effects on metabolism, behavior and immunity. Their impaired synthesis and production lead to adverse health effects. Some environmental toxicants, including phthalate esters (PAEs), are associated with endocrine disruption. These endocrine-disrupting chemicals (EDCs) also cause adrenal toxicity and alteration of GC biosynthesis and their functions. Using in silico tools of Schrodinger Maestro 9.4, we performed a molecular docking study of 32 ligands including PAEs of a known endocrine-disrupting potential with the selected enzymes of the GC biosynthesis pathway (GBP) such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β-HSD. Binding affinities of the PAEs were compared with known inhibitors of these enzymes. Amongst PAEs, diphenyl benzene-1, 2 - dicarboxylate (DPhP) showed the lowest docking score of -8.95616 kcal mol against CYP21A1. Besides, benzyl butyl benzene-1,2-dicarboxylate (BBzP), bis(7-methylnonyl) benzene-1,2 dicarboxylate (DIDP) and bis(2-ethylhexyl) benzene-1,2-dicarboxylate (DEHP) also showed comparable molecular interaction with enzymes of GBP. DPhP showed a significant molecular interaction with different enzymes of GBP such as CYP21A1, CYP11A1 and CYP11B2. These interactions mainly included H-bonding, hydrophobic, polar and van dar Waals' interactions. Interestingly, this in silico study revealed that certain PAEs have more inhibitory potential against enzymes of GBP than their respective known inhibitors. Such studies become more relevant in the risk assessment of exposure to mixtures of phthalate eaters. Copyright © 2016 John Wiley & Sons, Ltd.

Interdependence of Thyroid and Corticosteroid Signaling in Vertebrate Developmental Transitions

“…GC synthesis pathway is also a target. Different environmental toxicants, including phthalate esters together with bisphenols and their analogs pose deleterious effects on the biosynthesis of GC in vitro (Ahmad et al, 2017;Verma et al, 2018). These observations were confirmed in vivo using nitrate, a major anthropogenic contaminant in the FW environment.…”

Evaluation of the Removal of Selected Phthalic Acid Esters (PAEs) in Municipal Wastewater Treatment Plants Supported by Constructed Wetlands

“…Phthalic acid esters in living organisms can induce an effect like estrogens; therefore, PAEs are among the group of Endocrine Disrupting Compounds (ECDs). Data from in silico experiments have shown that some PAEs cause harmful effects on mammalian and non-mammalian organisms (e.g., [5]). For example, dibutyl phthalate (DBP) and benzyl butyl phthalate (BBP) and their metabolites were shown to be indicative of hemolysis and eryptosis in human erythrocytes [6].…”

“…(3) the determination of selected phthalates in raw and treated sewage samples from an MWWTP supported by CWs; (4) an assessment of the uptake of PAEs by plants used in CWs; (5) an evaluation of the possibility of using hydroponic cultivations for the effective removal of PAEs in MWWTPs.…”

Molecular interactions of dioxins and DLCs with the xenosensors (PXR and CAR): An in silico risk assessment approach

“…A number of researchers are involved in the assessment of deleterious effects of EDCs on the human physiological system . For such assessment, in silico tools have been proven to be of great worth . In the present study, the effect of dioxins and DLCs on PXR and CAR has been determined using an in silico study.…”

“…13,14 For such assessment, in silico tools have been proven to be of great worth. 15,16 In the present study, the effect of dioxins and DLCs on PXR and CAR has been determined using an in silico study. Results obtained were compared with the known inhibitors of these receptors.…”