Structure-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic.
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
Departments of Medicinal Chemistry, Structural Biology, Molecular Recognition, Protein Biochemistry, and Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
S K
SK
Thompson
W W
WW
Smith
B
B
Zhao
S M
SM
Halbert
T A
TA
Tomaszek
D G
DG
Tew
M A
MA
Levy
C A
CA
Janson
K J
KJ
DAlessio
M S
MS
McQueney
J
J
Kurdyla
C S
CS
Jones
R L
RL
DesJarlais
S S
SS
Abdel-Meguid
D F
DF
Veber
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D013329:Structure-Activity Relationship
D001565:Benzoates; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D002403:Cathepsins; D056657:Cathepsin K