Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.
Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.
Ghosh
Arun K
AK
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
Kumaragurubaran
Nagaswamy
N
Hong
Lin
L
Lei
Hui
H
Hussain
Khaja Azhar
KA
Liu
Chun-Feng
CF
Devasamudram
Thippeswamy
T
Weerasena
Vajira
V
Turner
Robert
R
Koelsch
Gerald
G
Bilcer
Geoffrey
G
Tang
Jordan
J
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry*
D008024:Ligands; D011480:Protease Inhibitors; D011506:Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human