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Structure-Based Virtual Screening Protocol for in Silico Identification of Potential Thyroid Disrupting Chemicals
Jin Zhang1, Afshan Begum1, Kristoffer Brännström1
1Department of Chemistry and ‡Department of Medical Biochemistry and Biophysics, Umeå University , SE-901 87 Umeå, Sweden.
Abstract:
Thyroid disruption by xenobiotics is associated with a broad spectrum of severe adverse outcomes. One possible molecular target of thyroid hormone disrupting chemicals (THDCs) is transthyretin (TTR), a thyroid hormone transporter in vertebrates. To better understand the interactions between TTR and THDCs, we determined the crystallographic structures of human TTR in complex with perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2,2',4,4'-tetrahydroxybenzophenone (BP2). The molecular interactions between the ligands and TTR were further characterized using molecular dynamics simulations. A structure-based virtual screening (VS) protocol was developed with the intention of providing an efficient tool for the discovery of novel TTR-binders from the Tox21 inventory. Among the 192 predicted binders, 12 representatives were selected, and their TTR binding affinities were studied with isothermal titration calorimetry, of which seven compounds had binding affinities between 0.26 and 100 μM. To elucidate structural details in their binding to TTR, crystal structures were determined of TTR in complex with four of the identified compounds including 2,6-dinitro-p-cresol, bisphenol S, clonixin, and triclopyr. The compounds were found to bind in the TTR hormone binding sites as predicted. Our results show that the developed VS protocol is able to successfully identify potential THDCs, and we suggest that it can be used to propose THDCs for future toxicological evaluations.
Insights
Thyroid hormone disrupting chemicals (THDCs) can interfere with transthyretin (TTR), a key transporter. This study developed a virtual screening method to identify new TTR-binding THDCs for toxicological assessment.
Area of Science:
- Environmental Toxicology
- Molecular Biology
- Structural Biology
Background:
- Xenobiotics can disrupt thyroid hormone homeostasis, leading to adverse health outcomes.
- Transthyretin (TTR) is a crucial vertebrate transporter of thyroid hormones and a potential target for thyroid hormone disrupting chemicals (THDCs).
Purpose of the Study:
- To investigate the molecular interactions between TTR and THDCs.
- To develop and validate a structure-based virtual screening (VS) protocol for identifying novel TTR-binding THDCs.
Main Methods:
- Determined crystallographic structures of human TTR complexed with PFOS, PFOA, and BP2.
- Employed molecular dynamics simulations to characterize ligand-TTR interactions.
- Developed and applied a VS protocol to screen the Tox21 chemical inventory for TTR binders.
- Validated predicted binders using isothermal titration calorimetry and determined crystal structures of TTR with identified compounds.
Main Results:
- Crystal structures revealed how PFOS, PFOA, and BP2 bind to the TTR hormone binding site.
- The VS protocol successfully predicted 192 potential TTR binders from the Tox21 inventory.
- Experimental validation confirmed binding for seven compounds, with affinities ranging from 0.26 to 100 μM.
- Crystal structures of TTR with four validated compounds (2,6-dinitro-p-cresol, bisphenol S, clonixin, triclopyr) elucidated their binding modes.
Conclusions:
- The developed VS protocol is an effective tool for identifying potential THDCs that bind to TTR.
- This method can prioritize compounds for future toxicological evaluations and aid in understanding TTR-mediated thyroid disruption.
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