Nuclear receptor ligands and ligand binding domains
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Accused Products
Abstract
The present invention provides new methods, particularly computational methods, and compositions for the generation of nuclear receptor synthetic ligands based on the three dimensional structure of nuclear receptors, particularly the thyroid receptor (herein referred to as “TR”). Also provided are crystals, nuclear receptor synthetic ligands, and related methods.
21 Citations
82 Claims
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1-60. -60. (canceled)
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61. A method of using a model of a nuclear hormone receptor, or ligand binding domain thereof, bound to a nuclear hormone receptor ligand, the method comprising:
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providing structural information corresponding to an atomic coordinate model of the nuclear hormone receptor, or ligand binding domain thereof, bound to the nuclear hormone receptor ligand; and
,accessing the structural information. - View Dependent Claims (64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)
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62. A method of determining whether a potential nuclear ligand is likely to bind to a nuclear hormone receptor ligand binding domain, the method comprising:
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accessing structural information corresponding to an atomic coordinate model of the nuclear hormone receptor ligand binding domain;
accessing structural information corresponding to the ligand; and
,modeling binding of the potential ligand to the nuclear hormone receptor ligand binding domain, thereby determining whether the potential ligand is likely to bind to the nuclear receptor ligand binding domain. - View Dependent Claims (63)
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75. A method for identifying a compound capable of selectively modulating the activity of a thyroid hormone receptor (TR) isoform, said method comprising:
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modeling test compounds that fit spatially and preferentially into a TR ligand binding domain (TR LBD) isoform of interest using an atomic structural model of a TR LBD isoform bound to a test compound, wherein said atomic structural model employs high resolution structural information corresponding to an atomic coordinate model of the thyroid hormone receptor, or ligand binding domain thereof, bound to the thyroid hormone receptor ligand, screening said test compounds in a biological assay for TR isoform activity characterized by binding of a test compound to a TR LBD isoform, and identifying a test compound that selectively modulates the activity of a TR isoform. - View Dependent Claims (76)
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77. A method for identifying a thyroid hormone receptor (TR) agonist or antagonist ligand, said method comprising the steps of:
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providing the atomic coordinates of a TR ligand binding domain (TR LBD) to a computerized modeling system, wherein said atomic coordinates are based on high resolution structural information corresponding to an atomic coordinate model of the thyroid hormone receptor, or ligand binding domain thereof, bound to the thyroid hormone receptor ligand;
modeling ligands which fit spatially into the TR LBD; and
identifying in a biological assay for TR activity a ligand which increases or decreases the activity of said TR, whereby a TR agonist or antagonist is identified. - View Dependent Claims (78)
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79. A method of identifying a compound that selectively modulates an activity of a thyroid hormone receptor (TR) compared to other nuclear hormone receptors, said method comprising:
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modeling compounds which fit spatially into a TR ligand binding domain (TR LBD) using an atomic structural model of a TR LBD, wherein said atomic structural model employs high resolution structural information corresponding to an atomic coordinate model of the thyroid hormone receptor, or ligand binding domain thereof, bound to the thyroid hormone receptor ligand;
selecting a compound comprising conformationally constrained structural features that interact with conformationally constrained residues of a TR LBD; and
,identifying in a biological assay for TR activity a compound that selectively binds to a TR LBD compared to other nuclear receptors, whereby a compound that selectively modulates a TR is identified. - View Dependent Claims (80)
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81. A method for identifying a thyroid hormone receptor (TR) agonist or antagonist ligand that selectively modulates an activity of a TR compared to other nuclear receptors, said method comprising the steps of:
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providing the atomic coordinates of a TR ligand binding domain (TR LBD) to a computerized modeling system, wherein said atomic coordinates are based on high resolution structural information corresponding to an atomic coordinate model of the thyroid hormone receptor, or ligand binding domain thereof, bound to the thyroid hormone receptor ligand;
modeling ligands which fit spatially into the TR LBD and which interact with conformationally constrained residues of a TR LBD conserved among TR isoforms; and
,identifying in a biological assay for TR activity a ligand which selectively binds to said TR and increases or decreases the activity of said TR, whereby a TR agonist or antagonist that selectively modulates the activity of a TR is identified. - View Dependent Claims (82)
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Specification