Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-2 (of 2 Records) |
Query Trace: Wheeler JS [original query] |
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3D QSAR studies of hydroxylated polychlorinated biphenyls as potential xenoestrogens
Ruiz P , Ingale K , Wheeler JS , Mumtaz M . Chemosphere 2015 144 2238-2246 Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERalpha) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERalpha. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para-positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals. |
Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: a QSAR comparative analysis
Ruiz P , Myshkin E , Quigley P , Faroon O , Wheeler JS , Mumtaz MM , Brennan RJ . SAR QSAR Environ Res 2013 24 (5) 393-416 Alternative methods, including quantitative structure-activity relationships (QSAR), are being used increasingly when appropriate data for toxicity evaluation of chemicals are not available. Approximately 40 mono-hydroxylated polychlorinated biphenyls (OH-PCBs) have been identified in humans. They represent a health and environmental concern because some of them have been shown to have agonist or antagonist interactions with human hormone receptors. This could lead to modulation of steroid hormone receptor pathways and endocrine system disruption. We performed QSAR analyses using available estrogenic activity (human estrogen receptor ER alpha) data for 71 OH-PCBs. The modelling was performed using multiple molecular descriptors including electronic, molecular, constitutional, topological, and geometrical endpoints. Multiple linear regressions and recursive partitioning were used to best fit descriptors. The results show that the position of the hydroxyl substitution, polarizability, and meta adjacent un-substituted carbon pairs at the phenolic ring contribute towards greater estrogenic activity for these chemicals. These comparative QSAR models may be used for predictive toxicity, and identification of health consequences of PCB metabolites that lack empirical data. Such information will help prioritize such molecules for additional testing, guide future basic laboratory research studies, and help the health/risk assessment community understand the complex nature of chemical mixtures. |
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