Pacofsky G J, Lackey K, Alligood K J, Berman J, Charifson P S, Crosby R M, Dorsey G F, Feldman P L, Gilmer T M, Hummel C W, Jordan S R, Mohr C, Shewchuk L M, Sternbach D D, Rodriguez M
Department of Medicinal Chemistry, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1998 May 21;41(11):1894-908. doi: 10.1021/jm970853a.
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.
本文描述了作为pp60c-src SH2结构域配体的二肽类似物的设计、合成及评估。确定了Ac-Tyr-Glu-N(n-C5H11)2（2）与该蛋白之间的关键结合相互作用，并以此作为我们基于结构的药物设计工作的基础。探究了二肽C端（11-27）和N端（51-69）部分变化的影响。还研究了总电荷降低的类似物（92-95）。我们证明了在适度的二肽框架中配对结构多样的亚基以增加类药性质而不牺牲结合亲和力的可行性。
