DOI: 10.1073/pnas.1131854100. Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking

Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking

10.1073/pnas.1131854100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Treatment of hyperthyroidism, a common clinical condition that can have serious manifestations in the elderly, has remained essentially unchanged for >30 years. Directly antagonizing the effect of the thyroid hormone at the receptor level may be a significant improvement for the treatment of hyperthyroid patients. We built a computer model of the thyroid hormone receptor (TR) ligand-binding domain in its predicted antagonist-bound conformation and used a virtual screening algorithm to select 100 TR antagonist candidates out of a library of >250,000 compounds. We were able to obtain 75 of the compounds selected in silico and studied their ability to act as antagonists by using cultured cells that express TR. Fourteen of these compounds were found to antagonize the effect of T3 on TR with IC 50 s ranging from 1.5 to 30 μM. A small virtual library of compounds, derived from the highest affinity antagonist (1-850) that could be rapidly synthesized, was generated. A second round of virtual screening identified new compounds with predicted increased antagonist activity. These second generation compounds were synthesized, and their ability to act as TR antagonists was confirmed by transfection and receptor binding experiments. The extreme structural diversity of the antagonist compounds shows how receptor-based virtual screening can identify diverse chemistries that comply with the structural rules of TR antagonism.

Bibliography

Schapira, M., Raaka, B. M., Das, S., Fan, L., Totrov, M., Zhou, Z., Wilson, S. R., Abagyan, R., & Samuels, H. H. (2003). Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking. Proceedings of the National Academy of Sciences, 100(12), 7354â7359.

Authors 9

Matthieu Schapira (first)
Bruce M. Raaka (additional)
Sharmistha Das (additional)
Li Fan (additional)
Maxim Totrov (additional)
Zhiguo Zhou (additional)
Stephen R. Wilson (additional)
Ruben Abagyan (additional)
Herbert H. Samuels (additional)

References 38 Referenced 137

DeGroot L. J. (2001) Endocrinology (Saunders Philadelphia) 4th Ed.
Braverman L. E. Utiger R. D. Ingbar S. H. & Werner S. C. eds. (2000) Werner and Ingbar's the Thyroid: A Fundamental and Clinical Text (Lippincott Williams & Wilkins Baltimore) 8th Ed.
Wilson J. D. ed. (1998) Textbook of Endocrinology (Saunders Philadelphia).
10.1152/physrev.2001.81.3.1097
10.1126/science.3283939
10.1210/edrv-11-2-201
Chambon, P. (1993) Gene 135, 223-228.8276261 / Gene (1993)
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Shiau, A. K., Barstad, D., Radek, J. T., Meyers, M. J., Nettles, K. W., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Agard, D. A. & Greene, G. L. (2002) Nat. Struct. Biol. 9, 359-364.11953755 / Nat. Struct. Biol. (2002)
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Molsoft (2002) ICM 2.8 Program Manual (Molsoft San Diego).
10.1006/jmbi.1994.1052
Totrov M. & Abagyan R. (1997) Proteins Suppl. 1 215-220.9485515 (10.1002/(SICI)1097-0134(1997)1+<215::AID-PROT29>3.0.CO;2-Q)
Totrov M. & Abagyan R. (2001) in Drug-Receptor Thermodynamics: Introduction and Applications ed. Raffa R. B. (Wiley New York) pp. 603-624.
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Abagyan R. Batalov S. Cardozo T. Totrov M. Webber J. & Zhou Y. (1997) Proteins Suppl. 1 29-37. (10.1002/(SICI)1097-0134(1997)1+<29::AID-PROT5>3.0.CO;2-J)

Dates

Type	When
Created	22 years, 2 months ago (June 10, 2003, 1:06 p.m.)
Deposited	3 years, 4 months ago (April 25, 2022, 9:26 p.m.)
Indexed	3 weeks, 2 days ago (Aug. 12, 2025, 6:14 p.m.)
Issued	22 years, 3 months ago (May 30, 2003)
Published	22 years, 3 months ago (May 30, 2003)
Published Online	22 years, 3 months ago (May 30, 2003)
Published Print	22 years, 2 months ago (June 10, 2003)

Funders 0

None

BibTeX

@article{Schapira_2003, title={Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1131854100}, DOI={10.1073/pnas.1131854100}, number={12}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Schapira, Matthieu and Raaka, Bruce M. and Das, Sharmistha and Fan, Li and Totrov, Maxim and Zhou, Zhiguo and Wilson, Stephen R. and Abagyan, Ruben and Samuels, Herbert H.}, year={2003}, month=may, pages={7354–7359} }

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