Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases.
A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
Coburn
Craig A
CA
Department of Medicinal Chemistry, Merck Research Laoratories, West Point, PA 19486-0004, USA. craig_coburn@merck.com
Stachel
Shawn J
SJ
Li
Yue-Ming
YM
Rush
Diane M
DM
Steele
Thomas G
TG
Chen-Dodson
Elizabeth
E
Holloway
M Katharine
MK
Xu
Min
M
Huang
Qian
Q
Lai
Ming-Tain
MT
DiMuzio
Jillian
J
Crouthamel
Ming-Chih
MC
Shi
Xiao-Ping
XP
Sardana
Vinod
V
Chen
Zhongguo
Z
Munshi
Sanjeev
S
Kuo
Lawrence
L
Makara
Gergely M
GM
Annis
D Allen
DA
Tadikonda
Praveen K
PK
Nash
Huw M
HM
Vacca
Joseph P
JP
Wang
Tong
T
D000081:Acetamides / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D001557:Benzenesulfonates / Q000737:chemistry*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D010450:Endopeptidases; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D001549:Benzamides; D001557:Benzenesulfonates; D011480:Protease Inhibitors; C494715:benzyl 5-((((5-aminopentyl)amino)carbonyl)methoxy)3-(((alpha-methyl-4-fluorobenzyl)amino)carbonyl)benzenesulfonate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases