Abstract
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. Methods:
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. Results:
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). Conclusion: 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.