化学
连接器
分子内力
肽
共价键
小分子
氢键
立体化学
蛋白质-蛋白质相互作用
分子
组合化学
生物化学
计算机科学
操作系统
有机化学
作者
Paulina Fortuna,Brian M. Linhares,Trupta Purohit,Jonathan Pollock,Tomasz Cierpicki,Jolanta Grembecka,Łukasz Berlicki
标识
DOI:10.1016/j.ejmech.2020.112748
摘要
The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effective cyclization strategy using a metathesis reaction allowed for a successfully large number of derivatives to be obtained. Subsequent optimization of the loop size, as well as N-terminal, central and C-terminal parts of the studied peptides resulted in structures exhibiting low nanomolar activities. A crystal structure of an inhibitor-menin complex revealed a compact conformation of the ligand molecule, which is stabilized not only by the introduction of a covalent linker but also three intramolecular hydrogen bonds. The inhibitor adopts a figure eight-like conformation, which perfectly fits the cleft of menin. We demonstrated that the development of compact, miniprotein-like structures is a highly effective approach for inhibition of protein-protein interactions.
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