Session Speaker

Virtual Screening for Cholesterol Biosynthesis Inhibitors
David Shiuan and Shing-Lei Wu
China

Many studies have demonstrated the role of elevated levels of serum cholesterol in the pathogenesis of atherosclerosis and coronary heart disease. Squalene synthase SQS catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis. We used human squalene synthase structure (PDB 1ezf) as the target for screening the inhibitors. The protein folds as a single domain and its binding site was predicted to be in a large channel in the middle of one face. ZINC database which contains over 13 million purchasable compounds in ready-to-dock 3D formats was filtered and screened using the docking tools of Discovery Studio and the Integrated Drug Design System IDDS. Several known bisphosphonate-type inhibitors were also included in the screening process as the positive controls. The screened compounds were further evaluated based on their potential toxicity and availability. Approximately ten lead compounds were purchased to determine their IC₅₀ values toward SQS.