Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors: Part I--discovery of two binding modes.
Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-alpha converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure-activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1'-S3' binding pockets, whereas mode B resides in the nonprime binding sites.
Zhu
Zhaoning
Z
Department of Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Zhaoning.Zhu@spcorp.com
Mazzola
Robert
R
Sinning
Lisa
L
McKittrick
Brian
B
Niu
Xiaoda
X
Lundell
Daniel
D
Sun
Jing
J
Orth
Peter
P
Guo
Zhuyan
Z
Madison
Vincent
V
Ingram
Richard
R
Beyer
Brian M
BM
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000072198:ADAM17 Protein; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D051722:ADAM Proteins; D000072198:ADAM17 Protein