Selective androgen receptor modulators and methods for their identification, design and use

A selective androgen receptor modulator, which modulator exhibits antagonist activity in a hormone-dependent tumor while exhibiting no activity or agonist activity against other, nontumor tissues containing the androgen receptor.

A molecule or molecular complex of the three-dimensional crystal structure as defined by the structural coordinates of Table A.

A molecule or molecular complex comprising all or any part of the ligand binding site defined by structure coordinates of AR-LBD amino acids V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, I737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, I869, L873, H874, F876, T877, F878, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906 and L907 according to Table A, or a mutant or homologue of said molecule or molecular complex.

A molecule or molecular complex comprising all or any part of the ligand binding site defined by structure coordinates of AR-LBD amino acids N705, W741, Q711, R752, F764, T877, M895 and I898 according to Table A, or a mutant or homologue of said molecule or molecular complex.

A machine-readable data storage medium comprising a data storage material encoded with machine readable data, wherein the data is defined by the structure coordinates of an AR-LBD/AR-LBD ligand or ligand complex according to Table A or a homologue of said complex, wherein said homologue comprises backbone atoms that have a root mean square deviation from the backbone atoms of the complex of not more than 3.0 Å.

A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data comprising a Fourier transform of at least a portion of the structural coordinates for an AR-LBD/AR-LBD ligand according to Table A;

• which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data, said first set of data and said second set of data.

A binding site in AR-LBD for an AR modulator in which a portion of said ligand is in van der Walls contact or hydrogen bonding contact with any portion or all of residues V685, L700, L701, S702, S703, L704, N705, E706, L707, G708, E709, Q711, A735, I737, Q738, Y739, S740, W741, M742, G743, L744, M745, V746, F747, A748, M749, G750, R752, Y763, F764, A765, L768, F770, M780, M787, I869, L873, H874, F876, T877, F878, L880, L881, V889, F891, P892, E893, M894, M895, A896, E897, I898, I899, S900, V901, Q902, V903, P904, K905, I906 or L907 of AR-LBD according to Table A.

A computational method of designing an androgen receptor synthetic ligand comprising:

• a. using a three dimensional model of a crystallized protein comprising an AR-LBD/AR-LBD ligand complex to determine at least one interacting amino acid of the AR-LBD that interacts with at least one first chemical moiety of the AR-LBD ligand;
• and
• b. selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety with a structure that either decreases or increases an interaction between said interacting amino acid and said second chemical moiety compared to said interaction between said interacting amino acid and said first chemical moiety.