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Androgen and Progesterone Receptors Are Targets for Bisphenol A (BPA), 4-Methyl-2,4-bis-(P-Hydroxyphenyl)Pent-1-Ene--A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A Computational Insight.

Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, AlBasri SF, Assiri MM, Beg MA - PLoS ONE (2015)

Bottom Line: For both the receptors the binding strength of MBP was maximum among the three compounds.Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction.The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

ABSTRACT
Exposure to toxic industrial chemicals that have capacity to disrupt the endocrine system, also known as endocrine disrupting chemicals (EDCs), has been increasingly associated with reproductive problems in human population. Bisphenol A (BPA; 4,4'-(propane-2,2-diyl)diphenol) and 4-tert-octylphenol (OP; 4-(1,1,3,3-tetramethylbutyl)phenol) are among the most common environmental contaminants possessing endocrine disruption properties and are present in plastics, epoxy resins, detergents and other commercial products of common personal and industrial use. A metabolite of BPA, 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is about 1000 times more biologically active compared to BPA. Epidemiological, clinical, and experimental studies have shown association of BPA and OP with adverse effects on male and female reproductive system in human and animals. The endocrine disruption activity can occur through multiple pathways including binding to steroid receptors. Androgen receptor (AR) and progesterone receptor (PR) are critical for reproductive tract growth and function. Structural binding characterization of BPA, MBP, and OP with AR and PR using molecular docking simulation approaches revealed novel interactions of BPA with PR, and MBP and OP with AR and PR. For BPA, MBP, and OP, five AR interacting residues Leu-701, Leu-704, Asn-705, Met-742, and Phe-764 overlapped with those of native AR ligand testosterone, and four PR interacting residues Leu-715, Leu-718, Met-756, and Met-759 overlapped with those of PR co-complex ligand, norethindrone. For both the receptors the binding strength of MBP was maximum among the three compounds. Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction. The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.

No MeSH data available.


Related in: MedlinePlus

Human progesterone receptor (PR) is illustrated in cartoon representation and bisphenol A (BPA), methylbishydroxyphenylpentene (MBP), 4-tert-octylphenol (OP), and the bound ligand norethindrone (NET) are in stick representation in different colors.
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pone.0138438.g004: Human progesterone receptor (PR) is illustrated in cartoon representation and bisphenol A (BPA), methylbishydroxyphenylpentene (MBP), 4-tert-octylphenol (OP), and the bound ligand norethindrone (NET) are in stick representation in different colors.

Mentions: The molecular docking study of BPA with PR identified the following BPA interacting residues of PR: Leu-715, Leu-718, Leu-721, Gln-725, Met-756, Met-759, Phe-778, Phe-794, and Leu-797 (Figs 4 and 5, Table 5). The indicated nine residues together formed 18 hydrophobic interactions and stabilized the BPA-PR complex. Further, the high values of the Dock score, binding energy, and dissociation constant also showed good quality of binding, however, binding energy, and dissociation constant were less compared to those of the bound ligand NET from PDB PR co-complex structure (Table 2). The residue Leu-718 was identified as the key interacting residue as it showed maximum number of hydrophobic contacts and maximum ΔASA due to BPA binding (Table 5). The comparison in binding of BPA to PR with the bound NET showed that all the BPA interacting residues were overlapping except Phe-778 and Phe-794 (Fig 5B). The overlapping of residues suggested that BPA has potential to occupy important residues in different molecular interactions and hence not making them available for binding of natural ligand to PR. Thus, BPA has potential for interference in the normal function of PR.


Androgen and Progesterone Receptors Are Targets for Bisphenol A (BPA), 4-Methyl-2,4-bis-(P-Hydroxyphenyl)Pent-1-Ene--A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A Computational Insight.

Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, AlBasri SF, Assiri MM, Beg MA - PLoS ONE (2015)

Human progesterone receptor (PR) is illustrated in cartoon representation and bisphenol A (BPA), methylbishydroxyphenylpentene (MBP), 4-tert-octylphenol (OP), and the bound ligand norethindrone (NET) are in stick representation in different colors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574962&req=5

pone.0138438.g004: Human progesterone receptor (PR) is illustrated in cartoon representation and bisphenol A (BPA), methylbishydroxyphenylpentene (MBP), 4-tert-octylphenol (OP), and the bound ligand norethindrone (NET) are in stick representation in different colors.
Mentions: The molecular docking study of BPA with PR identified the following BPA interacting residues of PR: Leu-715, Leu-718, Leu-721, Gln-725, Met-756, Met-759, Phe-778, Phe-794, and Leu-797 (Figs 4 and 5, Table 5). The indicated nine residues together formed 18 hydrophobic interactions and stabilized the BPA-PR complex. Further, the high values of the Dock score, binding energy, and dissociation constant also showed good quality of binding, however, binding energy, and dissociation constant were less compared to those of the bound ligand NET from PDB PR co-complex structure (Table 2). The residue Leu-718 was identified as the key interacting residue as it showed maximum number of hydrophobic contacts and maximum ΔASA due to BPA binding (Table 5). The comparison in binding of BPA to PR with the bound NET showed that all the BPA interacting residues were overlapping except Phe-778 and Phe-794 (Fig 5B). The overlapping of residues suggested that BPA has potential to occupy important residues in different molecular interactions and hence not making them available for binding of natural ligand to PR. Thus, BPA has potential for interference in the normal function of PR.

Bottom Line: For both the receptors the binding strength of MBP was maximum among the three compounds.Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction.The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

ABSTRACT
Exposure to toxic industrial chemicals that have capacity to disrupt the endocrine system, also known as endocrine disrupting chemicals (EDCs), has been increasingly associated with reproductive problems in human population. Bisphenol A (BPA; 4,4'-(propane-2,2-diyl)diphenol) and 4-tert-octylphenol (OP; 4-(1,1,3,3-tetramethylbutyl)phenol) are among the most common environmental contaminants possessing endocrine disruption properties and are present in plastics, epoxy resins, detergents and other commercial products of common personal and industrial use. A metabolite of BPA, 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is about 1000 times more biologically active compared to BPA. Epidemiological, clinical, and experimental studies have shown association of BPA and OP with adverse effects on male and female reproductive system in human and animals. The endocrine disruption activity can occur through multiple pathways including binding to steroid receptors. Androgen receptor (AR) and progesterone receptor (PR) are critical for reproductive tract growth and function. Structural binding characterization of BPA, MBP, and OP with AR and PR using molecular docking simulation approaches revealed novel interactions of BPA with PR, and MBP and OP with AR and PR. For BPA, MBP, and OP, five AR interacting residues Leu-701, Leu-704, Asn-705, Met-742, and Phe-764 overlapped with those of native AR ligand testosterone, and four PR interacting residues Leu-715, Leu-718, Met-756, and Met-759 overlapped with those of PR co-complex ligand, norethindrone. For both the receptors the binding strength of MBP was maximum among the three compounds. Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction. The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.

No MeSH data available.


Related in: MedlinePlus