Insight Mechanism of the Selective Lanosterol Synthase Inhibitor: Molecular Modeling, Docking and Density Functional Theory Approaches

Background: Lanosterol synthase (Oxidosqualene cyclase) is an enzyme, which plays a central role in cholesterol and sterols biosynthesis. Lanosterol synthase drugs are used to lower the level of cholesterol in the blood and treat wide variety of diseases like atherosclerosis, coronary heart diseases etc. Objective: There is a great interest in the identification of drugs that target this enzyme for anticholesteraemic agent using in silico tools. Methods: Ligand based pharmacophore model was developed using Discovery Studio 2.5. The best model was used as a tool to retrieve suitable molecule for Lanosterol synthase inhibitor from commercial database and Virtual screening of large commercially available databases to retrieve the best mole of Hypo1 using. Molecular docking was done using three different tools named as GOLD, GLIDE and AUTODOCK 4.0. Density functional theory approach and Density of State spectrum were carried out using Gaussian 09 and GAUSS SUM 3.0. Contribution of these methods in the selection of anticholesteraemic compounds has been discussed. Results: The best pharmacophore model was used to screen the commercial database. Totally 8 compounds were showed with the best orientation, binding mode and binging energy in the docking analyses. The orbital energies such as HOMO, LUMO and DOS spectrum for 8 hit compounds showed the energy gap that results in charge transfer and stability in the active site region. The results showed that our 8 potent leads could serve for further findings. Conclusion: In silico approaches, our 8 hit compounds could serve as the better understanding to design the novel lanosterol synthase inhibitors as anticholesteraemic activity. Keywords: Lanosterol synthase, pharmacophore modeling, virtual screening, molecular docking, density function theory, atherosclerosis.