Molecular Docking Studies of Squalen Synthase Inhibitors as Potential Anti Cardiovascular Disease Drugs: Insights into Drug-Protein Interaction Discovery

Squalene synthase (E.C, 2.5.1.21) catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to squalene, so that it is involved in the first step in cholesterol biosynthesis. Inhibition of squalene synthase is under consideration as an approach of decreasing cholesterol levels in the prevention of cardiovascular disease. Therefore squalene synthase is attractive object for the treatment of hypercholesterolemia, hypertriglyceridemia and coronary heart disease. Understanding the interaction of squalene synthase binding site with inhibitors is crucial for the development of pharmaceutical agents. At this aim, computer aided drug design is an applicable method that can study theses interactions and describe significant characteristics for squalene synthase binding site recognition. In the present work, we applied the molecular docking approach for 9 inhibitors of squalene synthase. Autodock Tools 4.2 was used in order to prepare the docking runs. After the docking runs, the final binding modes of the inhibitors were selected on the basis of the highest score or in other words best fit corresponding to the complex with the lowest free energy of binding. The docking results indicate that all inhibitors bind to squalene synthase active site. Our results clearly show that non polar interactions play a significant role in determining the binding free energy. The results also demonstrated that the inhibitor binding site is a hydrophobic pocket that completely is surrounded by the hydrophobic residue. Also, it was found that the inhibitor 6 (E5700) have the lowest binding free energy (-9.01 kcal/mol). The docking results will be useful for the structure-based drug design and the development of the pharmaceutical agents to treatment of coronary heart disease.