Patent ID: 7555415

Claim:
A method of designing or selecting a candidate agent that interacts with an estrogen receptor alpha (ERα), comprising: (a) utilizing the X-ray three-dimensional coordinates of a complex of an ERα ligand binding domain and a ligand according to Table 9 or Table 10, ± a root mean square deviation for alpha carbon atoms of not more than 1.5 Å, to generate a three-dimensional model, wherein the ligand is 4-[1-allyl-7-(trifluoromethyl)-1H-indazol-3-yl]benzene-1,3-diol) (Compound 1) or 4-[(8-Fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol) (Compound 2), and wherein the ligand is capable of forming one or more of the following interactions with the ERα ligand binding domain: (i) hydroxyl group of the A ring of Compound 1 forms hydrogen bonds with the side chains of Glu353 and Arg394 of SEQ ID NO:1, (ii) the hydroxyl group of Compound 2 forms hydrogen bonds with the side chain of Glu353 of SEQ ID NO:1, (iii) the phenyl group of Compound 1 and Compound 2 interacts with Phe404 of SEQ ID NO:1; (iv) Compound 1 and 2 interact indirectly with Phe425 and His524 of SEQ ID NO:1; (v) the indazole group of Compound 1 and the phenanthridine group of Compound 2 form hydrophobic interactions with the ERα ligand binding domain; or (vi) the allyl group of Compound 1 and the phenanthroline group of Compound 2 interact with Met421 of SEQ ID NO:1; (b) identifying the amino acid residues forming the ligand binding pocket of the ERα ligand binding domain from the three-dimensional model in step (a) in order to generate a three-dimensional representation of the ligand binding pocket of ERα, wherein the ligand binding pocket comprises amino acids Glu353, Arg394, Phe404, Met421, Phe425 and His524 of SEQ ID NO: 1, according to Table 9 or 10 ± a root mean square deviation for alpha carbon atoms of not more than 1.5 Å; and wherein said three-dimensional representation of the ligand binding pocket optionally has the ligand from step (a) present or absent; (c) employing said three-dimensional representation from step (b) to design or select said candidate agent such that the interactions from step (a) are maintained between the candidate agent and the ERα ligand binding pocket; (d) contacting said candidate agent with said ERα ligand binding domain to determine the ability of said candidate agent to interact or bind said ERα ligand binding domain; whereby the detection of the ability of said candidate agent to interact or bind said ERα ligand binding domain, thereby identifies said candidate agent as an agent that interacts with the ERα.