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Two‐Face, Two‐Turn α‐Helix Mimetics Based on a Cross‐Acridine Scaffold: Analogues of the Bim BH3 Domain
Author(s) -
Li Xiangqian,
Wang Ziqian,
Feng Yingang,
Song Ting,
Su Pengchen,
Chen Chengbin,
Chai Gaobo,
Yang Ying,
Zhang Zhichao
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402040
Subject(s) - scaffold , heteronuclear single quantum coherence spectroscopy , docking (animal) , scaffold protein , chemistry , acridine , peptide , triple helix , helix (gastropod) , biophysics , stereochemistry , nuclear magnetic resonance spectroscopy , combinatorial chemistry , computational biology , biochemistry , biology , computer science , signal transduction , nursing , organic chemistry , database , snail , medicine , ecology
The design of a cross‐acridine scaffold mimicking the i , i +3, i +5, and i +7 residues distributed over a two‐face, two‐turn α‐helix is described. Docking studies and 2D 1 H, 15 N HSQC NMR spectroscopy provide compelling evidence that compound 3 d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl‐1 and Bcl‐2 proteins ( K i 0.079 and 0.056 μ M , respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold.