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.
Thompson
S K
SK
Departments of Medicinal Chemistry, Structural Biology, Molecular Recognition, Protein Biochemistry, and Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Smith
W W
WW
Zhao
B
B
Halbert
S M
SM
Tomaszek
T A
TA
Tew
D G
DG
Levy
M A
MA
Janson
C A
CA
DAlessio
K J
KJ
McQueney
M S
MS
Kurdyla
J
J
Jones
C S
CS
DesJarlais
R L
RL
Abdel-Meguid
S S
SS
Veber
D F
DF
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