Glucocorticoid receptor modulators informed by crystallography lead to a new rationale for receptor selectivity, function, and implications for structure-based design.
The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane sulfonamides, is a potent anti-inflammatory agent with selectivity for the GR versus other steroid receptors and a differentiated gene expression profile versus clinical glucocorticoids (lower GR transactivation with comparable transrepression). A stereospecific synthesis of this chiral molecule provides the unique topology needed for biological activity and structural biology. In vivo activity of 10 in acute and chronic models of inflammation is equivalent to prednisolone. The crystal structure of compound 10 within the GR ligand binding domain (LBD) unveils a novel binding conformation distinct from the classic model adopted by cognate ligands. The overall conformation of the GR LBD/10 complex provides a new basis for binding, selectivity, and anti-inflammatory activity and a path for further insights into structure-based ligand design.
Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
Matthew W
MW
Carson
John G
JG
Luz
Chen
C
Suen
Chahrzad
C
Montrose
Richard
R
Zink
Xiaoping
X
Ruan
Christine
C
Cheng
Harlan
H
Cole
Mary D
MD
Adrian
Dan T
DT
Kohlman
Thomas
T
Mabry
Nancy
N
Snyder
Brad
B
Condon
Milan
M
Maletic
David
D
Clawson
Anna
A
Pustilnik
Michael J
MJ
Coghlan
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D001584:Benzoxepins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D002351:Carrageenan; D002460:Cell Line; D002908:Chronic Disease; D003094:Collagen; D018360:Crystallography, X-Ray; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001584:Benzoxepins; D008024:Ligands; C587725:N-(3-(1-(10-methoxy-6H-benzo(c)(1)benzoxepin-11-ylidene)propyl)phenyl)methanesulfonamide; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D002351:Carrageenan; D003094:Collagen