Potent dipeptide inhibitors of the pp60c-src SH2 domain.
The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.
Pacofsky
G J
GJ
Department of Medicinal Chemistry, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
Lackey
K
K
Alligood
K J
KJ
Berman
J
J
Charifson
P S
PS
Crosby
R M
RM
Dorsey
G F
GF
Feldman
P L
PL
Gilmer
T M
TM
Hummel
C W
CW
Jordan
S R
SR
Mohr
C
C
Shewchuk
L M
LM
Sternbach
D D
DD
Rodriguez
M
M
D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; C112425:acetyl-phosphotyrosyl-N,N-dipentylglutamamide; D016392:Proto-Oncogene Proteins pp60(c-src)