کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1364408 | 981536 | 2005 | 8 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Evaluation of macrocyclic Grb2 SH2 domain-binding peptide mimetics prepared by ring-closing metathesis of C-terminal allylglycines with an N-terminal β-vinyl-substituted phosphotyrosyl mimetic Evaluation of macrocyclic Grb2 SH2 domain-binding peptide mimetics prepared by ring-closing metathesis of C-terminal allylglycines with an N-terminal β-vinyl-substituted phosphotyrosyl mimetic](/preview/png/1364408.png)
Preferential binding of ligands to Grb2 SH2 domains in β-bend conformations has made peptide cyclization a logical means of effecting affinity enhancement. This is based on the concept that constraint of open-chain sequences to bend geometries may reduce entropy penalties of binding. The current study extends this approach by undertaking ring-closing metathesis (RCM) macrocyclization between i and i + 3 residues through a process involving allylglycines and β-vinyl-functionalized residues. Ring closure in this fashion results in minimal macrocyclic tetrapeptide mimetics. The predominant effects of such macrocyclization on Grb2 SH2 domain binding affinity were increases in rates of association (from 7- to 16-fold) relative to an open-chain congener, while decreases in dissociation rates were less pronounced (approximately 2-fold). The significant increases in association rates were consistent with pre-ordering of solution conformations to near those required for binding. Data from NMR experiments and molecular modeling simulations were used to interpret the binding results. An understanding of the conformational consequences of such i to i + 3 ring closure may facilitate its application to other systems where bend geometries are desired.
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Journal: Bioorganic & Medicinal Chemistry - Volume 13, Issue 7, 1 April 2005, Pages 2431–2438