Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor
Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved September 3, 2009
Abstract
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.
Data Availability
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3K22 and 3K23).
Acknowledgments.
We thank the following for their valuable contributions to this work: David Brown, Matilde Caivano, Margaret Clackers, Anette Miles-Williams, and Rosemary Sasse (screening and compound profiling); Bhavesh Patel, Heather Barnett, Karl Collins, and Natalie Wellaway (chemistry); James Gray, David Lugo, and Cesar Ramirez-Molina (drug metabolism); Eugene Stewart (computational chemistry); and Eric Hortense and Steve Jackson (analytical chemistry).
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© 2009.
Data Availability
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3K22 and 3K23).
Submission history
Received: August 13, 2009
Published online: October 27, 2009
Published in issue: October 27, 2009
Keywords
Acknowledgments
We thank the following for their valuable contributions to this work: David Brown, Matilde Caivano, Margaret Clackers, Anette Miles-Williams, and Rosemary Sasse (screening and compound profiling); Bhavesh Patel, Heather Barnett, Karl Collins, and Natalie Wellaway (chemistry); James Gray, David Lugo, and Cesar Ramirez-Molina (drug metabolism); Eugene Stewart (computational chemistry); and Eric Hortense and Steve Jackson (analytical chemistry).
Notes
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0909125106/DCSupplemental.
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Competing Interests
The authors declare no conflict of interest.
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Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor, Proc. Natl. Acad. Sci. U.S.A.
106 (43) 18114-18119,
https://doi.org/10.1073/pnas.0909125106
(2009).
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