NMR screening applied to the fragment-based generation of inhibitors of creatine kinase exploiting a new interaction proximate to the ATP binding site

被引:15
作者
Bretonnet, Anne-Sophie [1 ]
Jochum, Anne [1 ]
Walker, Olivier [1 ]
Krimm, Isabelle [1 ]
Goekjian, Peter [1 ]
Marcillat, Olivier [1 ]
Lancelin, Jean-Marc [1 ]
机构
[1] Univ Lyon 1, Lab RMN & Spectrometrie Masse Biomol, UMR CNRS 5180 Sci Analyt, ESCPE Lyon,Lab Chim Organ Glycochime 2, F-69622 Villeurbanne, France
关键词
D O I
10.1021/jm061460r
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Using an in-house fragment NMR library, we identified a set of ligands that bind rabbit muscular creatine kinase, an enzyme involved in key ATP-dependent processes. The ligands docked to the crystal structures of creatine kinase indicated that a phenylfuroic acid could enter into a pocket adjacent to the nucleotide binding site. This fragment served as an anchor to develop in silico a series of potential inhibitors which could partly access the nucleotide binding site. The short synthesis of only four derivatives provided entirely novel hit compounds that reversibly inhibit creatine kinase at micromolar concentrations with a mixed ATP-competitive/noncompetitive mechanism in agreement with the structural model of the inhibited enzyme. These initial biologically active compounds are novel and modular and exploit a new interaction proximate to the ATP binding site.
引用
收藏
页码:1865 / 1875
页数:11
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