Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene Cyclase

• Published in: Journal of medicinal chemistry Vol. 46; no. 11; pp. 2083 - 2092
• Main Authors: Lenhart, Alexander, Reinert, Dirk J, Aebi, Johannes D, Dehmlow, Henrietta, Morand, Oliver H, Schulz, Georg E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 22.05.2003
• Subjects: Amines - chemistry; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Bacillaceae - chemistry; Benzene Derivatives - chemistry; Benzophenones - chemistry; Benzophenones - pharmacology; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Cyclopropanes - chemistry; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Humans; In Vitro Techniques; Intramolecular Transferases - antagonists & inhibitors; Intramolecular Transferases - chemistry; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Sulfur nitrogen heterocycle; Ether; Enzyme; Enzyme inhibitor; Homology; Cycloartenol synthase; Oxygen heterocycle; Ketone; In vitro; Modeling; Cholesterol; Isomerases; Synthetic product; Structure activity relation; Molecular model; Intramolecular transferases; Tertiary amine; Bicyclic compound; Benzenic compound; Bromine Organic compounds; Aromatic compound; Benzofuran derivatives; Antilipemic agent
• ISSN: 0022-2623; 1520-4804
• 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.