Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Journal Article · Fri Sep 17 04:00:00 EDT 2010 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.0909125106· OSTI ID:1006160

Biggadike, Keith; Bledsoe, Randy K; Coe, Diane M; Cooper, Tony W.J.; House, David; Macdonald, Simon J.F.; Madauss, Kevin P; McLay, Iain M; Shipley, Tracy J; Taylor, Simon J; Tran, Thuy B; Uings, Iain J; Weller, Victoria; Williams, Shawn P

Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the 'meta' channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1006160
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (43) ; 10, 2009 Vol. 106; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ACCURACY
AMIDES
COMPUTERS
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
DESIGN
GLUCOCORTICOIDS
INDAZOLES
OCCUPATIONS
PYRROLIDONES
SIMULATION