Saudi-KAU Coupled Global Climate Model: Description and Performance

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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.

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

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.

<p>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.</p

The human progesterone receptor (PR) residues interacting with 4-tert-octylphenol (OP) are listed with the number of hydrophobic interactions and loss in Accessible Surface Area (ΔASA).

<p>The ranking of residues on the basis of ΔASA is indicated by superscripts with the value of ΔASA.</p

Comparative analysis of methylbishydroxyphenylpentene (MBP) binding to human androgen receptor (AR) and progesterone receptor (PR).

<p>Panel A and Panel B display the interacting residues of AR and PR, respectively, with MBP when MBP is kept in the same orientation. On visual analyses in PyMol, the interacting residues were superimposed keeping the docked MBP in same orientation. The residues of the two receptors which were falling at similar location with respect to MBP were encircled in similar color.</p

Comparative binding analysis of A: natural ligand testosterone (TST) with B: bisphenol A (BPA), C: methylbishydroxyphenylpentene (MBP), and D: 4-tert-octylphenol (OP) in the binding site of human androgen receptor (AR).

<p>The hydrogen bonds are shown as green-dashed lines with indicated bond lengths and the residues involved in hydrophobic interactions are shown as red arcs. The interacting residues which are common for all the ligands are encircled.</p

The human progesterone receptor (PR) residues interacting with bisphenol A (BPA) are listed with the number of hydrophobic interactions and loss in Accessible Surface Area (ΔASA).

<p>The ranking of residues on the basis of ΔASA is indicated by superscripts with the value of ΔASA.</p

The human progesterone receptor (PR) residues interacting with bisphenol A metabolite methylbishydroxyphenylpentene (MBP) are listed with the number of hydrophobic interactions and loss in Accessible Surface Area (ΔASA).

<p>The ranking of residues on the basis of ΔASA is indicated by superscripts with the value of ΔASA.</p

The human androgen receptor (AR) residues interacting with 4-tert-octylphenol (OP) are listed with the number of hydrophobic interactions and loss in Accessible Surface Area (ΔASA).

<p>The ranking of residues on the basis of ΔASA is indicated by superscripts with the value of ΔASA.</p

Sequence alignment of ligand binding sites of human androgen receptor (AR) and progesterone receptor (PR).

<p>The amino acids showing sequence identity in both the receptors are shown as white text with blue background, whereas, the rest of the amino acids are shown in black text. The initial and final position of each receptor in the alignment is also provided. The position-equivalent-residues (residues of both receptors falling at similar column position in the alignment) overlapping among the interacting residues of methylbishydroxyphenylpentene (MBP), are marked by red triangles.</p