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Open AccessArticle
Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors
by
Saptarshi Roy
Saptarshi Roy 1,
James Moran
James Moran 2,†,
Keerthana Danasekaran
Keerthana Danasekaran 3,†,
Kate O’Brien
Kate O’Brien 4 and
Sivanesan Dakshanamurthy
Sivanesan Dakshanamurthy 5,*
1
College of Humanities and Sciences, Virginia Commonwealth University, 907 Floyd Ave, Richmond, VA 23284, USA
2
College of Arts & Sciences, Georgetown University, 3700 O St NW, Washington, DC 20057, USA
3
College of Arts and Sciences, University of Rochester, 500 Joseph C. Wilson Blvd, Rochester, NY 14627, USA
4
Davidson College, 405 N Main St, Davidson, NC 28035, USA
5
Lombardi Comprehensive Cancer Center, Georgetown University, 3700 O St NW, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(15), 8241; https://doi.org/10.3390/ijms25158241 (registering DOI)
Submission received: 4 July 2024
/
Revised: 26 July 2024
/
Accepted: 26 July 2024
/
Published: 28 July 2024
Abstract
Despite their significant impact, comprehensive screenings and detailed analyses of per- and polyfluoroalkyl substance (PFAS) binding strengths at the orthosteric and allosteric sites of NRs are currently lacking. This study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with the nuclear receptors (NRs) vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). Advanced docking simulations were used to screen 9507 PFAS chemicals at the orthosteric and allosteric sites of PPARγ, PXR, VDR, and ERα. All receptors exhibited strong binding interactions at the orthosteric and allosteric site with a significant number of PFAS. We verified the accuracy of the docking protocol through multiple docking controls and validations. A mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and endogenous ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. The purpose of this study is to explore the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study further emphasizes the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of therapeutic strategies that target nuclear receptors.
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MDPI and ACS Style
Roy, S.; Moran, J.; Danasekaran, K.; O’Brien, K.; Dakshanamurthy, S.
Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors. Int. J. Mol. Sci. 2024, 25, 8241.
https://doi.org/10.3390/ijms25158241
AMA Style
Roy S, Moran J, Danasekaran K, O’Brien K, Dakshanamurthy S.
Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors. International Journal of Molecular Sciences. 2024; 25(15):8241.
https://doi.org/10.3390/ijms25158241
Chicago/Turabian Style
Roy, Saptarshi, James Moran, Keerthana Danasekaran, Kate O’Brien, and Sivanesan Dakshanamurthy.
2024. "Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors" International Journal of Molecular Sciences 25, no. 15: 8241.
https://doi.org/10.3390/ijms25158241
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