Nuclear receptor ligands and ligand binding domains

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.

1 - 60 . (canceled)  
     
     
         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: 
 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.    
     
     
         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: 
 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.    
     
     
         63 . The method of  claim 62 , wherein modeling binding of the potential ligand comprises modeling whether the ligand binding domain folds around the potential ligand to form a buried ligand binding cavity.  
     
     
         64 . The method of  claim 61  or  62 , wherein, in the atomic coordinate model, the nuclear receptor folds around the ligand or potential ligand to form a buried ligand binding cavity.  
     
     
         65 . The method of  claim 61  or  62 , wherein the atomic coordinate model of the nuclear hormone receptor ligand binding domain comprises structural information for a bound ligand.  
     
     
         66 . The method of  claim 61  or  62 , wherein the structural information comprises information corresponding to data from Appendix 3, 4, 5, 6, 7 or 8.  
     
     
         67 . The method of  claim 61  or  62 , wherein accessing the structural information comprises performing a Forrier transform of crystallograpic data corresponding to the nuclear receptor, the nuclear receptor ligand binding domain, or the nuclear receptor bound to the ligand at the nuclear receptor ligand binding domain.  
     
     
         68 . The method of  claim 61  or  62 , comprising modeling which amino acid or amino acids of the nuclear receptor or nuclear receptor ligand binding domain interact with at least a first chemical moeity of the ligand.  
     
     
         69 . The method of  claim 68 , further comprising designing a modified ligand, which modified ligand is selected to increase or decrease a modeled interaction between the amino acid or amino acids and the first chemical moiety.  
     
     
         70 . The method of  claim 61  or  62 , comprising crystalizing the nuclear hormone receptor bound to the nuclear receptor ligand, wherein the structural information is derived from a crystal structure of the resulting crystal.  
     
     
         71 . The method of  claim 61  or  62 , wherein the ligand is a computationally designed ligand.  
     
     
         72 . The method of  claim 61  or  62 , wherein the ligand is a compound of Formula 1.  
     
     
         73 . The method of  claim 61  or  62 , wherein the nuclear hormone receptor is a TR receptor.  
     
     
         74 . The method of  claim 61  or  62 , wherein the nuclear hormone receptor is selected from the group consisting of: a glucocorticoid receptor, an androgen receptor, a progestin receptor, an estrogen receptor, a vitamin D receptor, a retinoid receptor, an icosanoid receptor, and a peroxisome receptor.  
     
     
         75 . A method for identifying a compound capable of selectively modulating the activity of a thyroid hormone receptor (TR) isoform, said method comprising: 
 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.    
     
     
         76 . The method of  claim 75 , wherein said atomic structural model employs high resolution structural information corresponding to data from Appendix 3, 4, 5, 6, 7 or 8.  
     
     
         77 . A method for identifying a thyroid hormone receptor (TR) agonist or antagonist ligand, said method comprising the steps of: 
 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.    
     
     
         78 . The method of  claim 77 , wherein said atomic coordinates are based on data from Appendix 3, 4, 5, 6, 7 or 8.  
     
     
         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: 
 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.    
     
     
         80 . The method of  claim 79 , wherein said atomic structural model employs high resolution structural information corresponding to data from Appendix 3, 4, 5, 6, 7 or 8.  
     
     
         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: 
 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.    
     
     
         82 . The method of  claim 81 , wherein said atomic coordinates are based on data from Appendix 3, 4, 5, 6, 7 or 8.