**5. Other structure-based design considerations**

In addition to exploring the development of partial agonists, structure-based approaches continue to play an important role in the identification of new ligands via virtual screening approaches and other compound optimization tasks. An important lesson in this regard has been our change in understanding the dynamic nature of the steroid-receptor binding pocket. We have seen examples of extensive induced fits for amongst others the glucocorticoid receptor which is able to bind ligands beyond the conventional confines of its binding pocket whilst remaining in an agonistic conformation (Biggadike et al, 2009;Madauss et al, 2008;Suino-Powell et al, 2008). The pocket, behind the crucial helix-3 and helix-5 binding residues, Gln570 and Arg611, is normally water filled. It has already been demonstrated to be a viable ligand-binding region with the potential to improve ligand potency. An interesting note regarding the exploration of the pocket is that GSK report difficulty in combining the use of this pocket with the maintenance of partial agonism (Biggadike et al, 2009). PR has been shown to adapt to steroids baring bulky 17α groups (Madauss et al, 2004) and Trp741 in AR adapts to different ligands, adopting a new position to open an additional channel in the receptor (Bohl et al, 2005).

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors 231

Bohl CE, Miller DD, Chen J, Bell CE, and Dalton JT. 2005. Structural basis for

Bohl CE, Wu Z, Miller DD, Bell CE, and Dalton JT. 2007. Crystal structure of the T877A

Bourguet W, Germain P, and Gronemeyer H. 2000. Nuclear receptor ligand-binding

Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene

Cantin L, Faucher F, Couture JF, de Jesus-Tran KP, Legrand P, Ciobanu LC, Frechette Y,

Dykstra KD, Guo L, Birzin ET, Chan W, Yang YT, Hayes EC, DaSilva CA, Pai LY, Mosley

Fagart J, Huyet J, Pinon GM, Rochel M, Mayer C, and Rafestin-Oblin ME. 2005. Crystal

Fagart J, Wurtz JM, Souque A, Hellal-Levy C, Moras D, and Rafestin-Oblin ME. 1998. Antagonism in the human mineralocorticoid receptor. *EMBO J.* 17 (12): 3317-3325. Gao W, and Dalton JT. 2007. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). *Drug Discov. Today* 12 (5-6): 241-248. Heldring N, Pawson T, McDonnell D, Treuter E, Gustafsson JA, and Pike AC. 2007.

Hellal-Levy C, Fagart J, Souque A, Wurtz JM, Moras D, and Rafestin-Oblin ME. 2000.

Hillmann AG, Ramdas J, Multanen K, Norman MR, and Harmon JM. 2000. Glucocorticoid

Hubbard RE, Pike AC, Brzozowski AM, Walton J, Bonn T, Gustafsson JA, and Carlquist M.

oestrogen receptor isoforms. *Eur. J. Cancer* 36 Suppl 4: S17-S18.

human mineralocorticoid receptor. *Mol. Endocrinol.* 14 (8): 1210-1221. Hermkens PH, Kamp S, Lusher S, and Veeneman GH. 2006. Non-steroidal steroid receptor

selective ligands for ERalpha. *Bioorg. Med. Chem. Lett.* 17 (8): 2322-2328. Egea PF, Klaholz BP, and Moras D. 2000. Ligand-protein interactions in nuclear receptors of

antagonism in the oestrogen receptor. *Nature* 389 (6652): 753-758.

based drug design. *J. Biol. Chem.* 282 (18): 13648-13655.

implications. *Trends Pharmacol. Sci.* 21 (10): 381-388.

*J. Biol. Chem.* 282 (42): 30910-30919.

hormones. *FEBS Lett.* 476 (1-2): 62-67.

receptors. *J. Biol. Chem.* 282 (14): 10449-10455.

*Struct. Mol. Biol.* 12 (6): 554-555.

modulators. *IDrugs.* 9 (7): 488-494.

60 (7): 2056-2062.

(45): 37747-37754.

accommodation of nonsteroidal ligands in the androgen receptor. *J. Biol. Chem.* 280

human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-

domains: three-dimensional structures, molecular interactions and pharmacological

GL, Gustafsson JA, and Carlquist M. 1997. Molecular basis of agonism and

Labrecque R, Singh SM, Labrie F, and Breton R. 2007. Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12.

RT, Kraker B, Fitzgerald PM, Dininno F, Rohrer SP, Schaeffer JM, and Hammond ML. 2007. Estrogen receptor ligands. Part 16: 2-Aryl indoles as highly subtype

structure of a mutant mineralocorticoid receptor responsible for hypertension. *Nat.* 

Structural insights into corepressor recognition by antagonist-bound estrogen

Crucial role of the H11-H12 loop in stabilizing the active conformation of the

receptor gene mutations in leukemic cells acquired in vitro and in vivo. *Cancer Res.*

2000. Structural insights into the mechanisms of agonism and antagonism in
