Lenhart Alexander, Reinert Dirk J, Aebi Johannes D, Dehmlow Henrietta, Morand Oliver H, Schulz Georg E
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstrasse 21, Freiburg im Breisgau 79104, Germany.
J Med Chem. 2003 May 22;46(11):2083-92. doi: 10.1021/jm0211218.
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.
作为降胆固醇药物设计的11种人氧化角鲨烯环化酶抑制剂与嗜酸 Alicyclobacillus acidocaldarius 的鲨烯-藿烯环化酶的结合结构已被确定，该酶是人类酶唯一已知结构的同源物。通过共结晶产生复合物，并通过X射线衍射分析阐明结构。所有抑制剂都结合在大的活性中心腔内。根据这11种以及其他17种抑制剂的IC50值，展示并讨论了详细的结合结构。它们为细菌酶的抑制提供了一致的情况，并可用于调整和改进人类酶的同源模型。两种酶的详细活性中心结构差异太大，无法显示IC50相关性。
