title: Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking.
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 IC50s ranging from 1.5 to 30 microM. 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.
authors.affiliation: Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA. matthieu@molsoft.com
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Raaka
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Das
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhou
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wilson
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D006980:Hyperthyroidism / Q000188:drug therapy / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine