Patent ID: 7496489
Filing Date: 2009-02-24
Classification: C07K

Abstract:
1. A method of designing or selecting a non-steroidal candidate agent that interacts with a progesterone receptor, comprising: (a) utilizing the three-dimensional structural coordinates of the progesterone receptor ligand binding domain:non-steroidal ligand complex of Table 2 ± a root mean square deviation for alpha carbon atoms of not more than 1.5 Å, to generate a three-dimensional model wherein said non-steroidal ligand from Table 2 forms a favorable hydrogen bond, hydrophobic and/or electrostatic interaction between said non-steroid ligand and Asn719 and Gln725, and between one or more of Leu797, Arg766, Thr894 or Cys891; (b) identifying the amino acid residues forming a non-steroidal ligand binding pocket of the progesterone receptor ligand binding domain from the three-dimensional model in step (a) in order to generate a three-dimensional representation of the non-steroidal ligand binding pocket, wherein the non-steroidal ligand binding pocket comprises amino acids Ile699, Ala701, Leu714, Leu715, Leu718, Asn719, Leu721, Gln725, Trp755, Met756, Met759, Val760, Leu763, Arg766, Ser767, Tyr777, Phe778, Ala779, Leu782, Phe794, Leu797, Cys798, Met801, Ile804, Leu887, His888, Tyr890, Cys891, Asn893, Thr894, Phe895, Ser898, Leu901, Val903, Phe905, Met909, Ile913, and Leu917 according to Table 2, ± a root mean square deviation for alpha carbon atoms of not more than 1.5 Å, and wherein said three-dimensional representation of the non-steroidal ligand binding pocket optionally has the non-steroidal 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 favorable interactions from step (a) are maintained between the candidate non-steroidal ligand and the progesterone receptor ligand binding pocket; (d) synthesizing said candidate agent; and (e) contacting said candidate agent with said progesterone receptor ligand binding domain to determine the ability of said candidate agent to interact or bind said progesterone receptor ligand binding domain; whereby the detection of the ability of said candidate agent to interact or bind said progesterone receptor ligand binding domain thereby identifies said candidate agent as an agent that interacts with the progesterone receptor.