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

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1];  [2]
  1. (GSKNC)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1149625
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; Journal Volume: 106; Journal Issue: (43) ; 10, 2009
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Biggadike, Keith, Bledsoe, Randy K., Coe, Diane M., Cooper, Tony W.J., House, David, Iannone, Marie A., 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., and GSK). Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor. United States: N. p., 2014. Web. doi:10.1073/pnas.0909125106.
Biggadike, Keith, Bledsoe, Randy K., Coe, Diane M., Cooper, Tony W.J., House, David, Iannone, Marie A., 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., & GSK). Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor. United States. doi:10.1073/pnas.0909125106.
Biggadike, Keith, Bledsoe, Randy K., Coe, Diane M., Cooper, Tony W.J., House, David, Iannone, Marie A., 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., and GSK). Wed . "Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor". United States. doi:10.1073/pnas.0909125106.
@article{osti_1149625,
title = {Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor},
author = {Biggadike, Keith and Bledsoe, Randy K. and Coe, Diane M. and Cooper, Tony W.J. and House, David and Iannone, Marie A. and Macdonald, Simon J.F. and Madauss, Kevin P. and McLay, Iain M. and Shipley, Tracy J. and Taylor, Simon J. and Tran, Thuy B. and Uings, Iain J. and Weller, Victoria and Williams, Shawn P. and GSK)},
abstractNote = {},
doi = {10.1073/pnas.0909125106},
journal = {Proc. Natl. Acad. Sci. USA},
number = (43) ; 10, 2009,
volume = 106,
place = {United States},
year = {Wed Aug 13 00:00:00 EDT 2014},
month = {Wed Aug 13 00:00:00 EDT 2014}
}
  • 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.more » 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.« less
  • An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17{alpha} furoate ester to occupy more fully the lipophilic 17{alpha} pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.
  • G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the {beta}{sub 2} adrenergic receptor ({beta}{sub 2}AR) is one of the most extensively studied. Previously, the X-ray crystal structure of {beta}{sub 2}AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational differences, we determined the crystal structures of a previously described engineered {beta}{sub 2}AR construct in complex with two inverse agonists: ICI 118,551 (2.8 {angstrom}),more » a recently described compound (2.8 {angstrom}) (Kolb et al, 2009), and the antagonist alprenolol (3.1 {angstrom}). The structures show the same overall fold observed for the previous {beta}{sub 2}AR structures and demonstrate that the ligand binding site can accommodate compounds of different chemical and pharmacological properties with only minor local structural rearrangements. All three compounds contain a hydroxy-amine motif that establishes a conserved hydrogen bond network with the receptor and chemically diverse aromatic moieties that form distinct interactions with {beta}{sub 2}AR. Furthermore, receptor ligand cross-docking experiments revealed that a single {beta}{sub 2}AR complex can be suitable for docking of a range of antagonists and inverse agonists but also indicate that additional ligand-receptor structures may be useful to further improve performance for in-silico docking or lead-optimization in drug design.« less
  • The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).