title: Potent dipeptide inhibitors of the pp60c-src SH2 domain.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Pacofsky
authors.forename: K
authors.initials: K
authors.lastname: Lackey
authors.forename: K J
authors.initials: KJ
authors.lastname: Alligood
authors.forename: J
authors.initials: J
authors.lastname: Berman
authors.forename: P S
authors.initials: PS
authors.lastname: Charifson
authors.forename: R M
authors.initials: RM
authors.lastname: Crosby
authors.forename: G F
authors.initials: GF
authors.lastname: Dorsey
authors.forename: P L
authors.initials: PL
authors.lastname: Feldman
authors.forename: T M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: C W
authors.initials: CW
authors.lastname: Hummel
authors.forename: S R
authors.initials: SR
authors.lastname: Jordan
authors.forename: C
authors.initials: C
authors.lastname: Mohr
authors.forename: L M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: D D
authors.initials: DD
authors.lastname: Sternbach
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: 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
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; C112425:acetyl-phosphotyrosyl-N,N-dipentylglutamamide; D016392:Proto-Oncogene Proteins pp60(c-src)