Binding structures and potencies of oxidosqualene cyclase inhibitors with the homologous squalene-hopene cyclase

被引:45
作者
Lenhart, A
Reinert, DJ
Aebi, JD
Dehmlow, H
Morand, OH
Schulz, GE
机构
[1] Univ Freiburg, Inst Organ Chem & Biochem, D-79104 Freiburg, Germany
[2] Hoffmann La Roche Ltd, Preclin Res, Div Pharmaceut, CH-4070 Basel, Switzerland
关键词
D O I
10.1021/jm0211218
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the structures were elucidated by X-ray diffraction analyses. All inhibitors were bound in the large active center cavity. The detailed binding structures are presented and discussed in the light of the IC50 values of these 11 as well as 17 other inhibitors. They provide a consistent picture for the inhibition of the bacterial enzyme and can be used to adjust and improve homology models of the human enzyme. The detailed active center structures of the two enzymes are too different to show an IC50 correlation.
引用
收藏
页码:2083 / 2092
页数:10
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