Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators.
Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring. We found that hydrophilic B-ring para-substituted analogs exhibit an additional region of hydrogen bonding not seen with steroidal compounds and that multiple halogen substitutions affect the B-ring conformation and aromatic interactions with Trp741. This information elucidates interactions important for high AR binding affinity and provides new insight for structure-based drug design.
Bohl
Casey E
CE
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 242 L.M. Parks Hall, Columbus, OH 43210, USA.
Wu
Zengru
Z
Chen
Jiyun
J
Mohler
Michael L
ML
Yang
Jun
J
Hwang
Dong Jin
DJ
Mustafa
Suni
S
Miller
Duane D
DD
Bell
Charles E
CE
Dalton
James T
JT
D000577:Amides / Q000037:antagonists & inhibitors / Q000737:chemistry*; D002100:Cachexia / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D008956:Models, Chemical; D008968:Molecular Conformation; D009132:Muscles / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*
D000577:Amides; D008024:Ligands; D011944:Receptors, Androgen; C034666:propionamide