Introduction: In the present research work, a pharmacophore based virtual screening was
performed using Discovery Studio 2.1 for the discovery of some novel molecules as inhibitors of
Squalene Synthase Enzyme, a key enzyme in cholesterol biosynthetic pathway.
Methods: A quantitative pharmacophore HypoGen was generated and the best HypoGen had two ring
aromatic and one hydrogen bond acceptor lipid features. The best HypoGen showed a very good correlation
coefficient (r = 0.901) with satisfactory cost analysis. Furthermore, the HypoGen was validated
externally by predicting the activity of test set. The developed model was found to be predictive as it
showed low error of prediction for test set molecules. The developed model was used as a search query
for virtually screening two chemical databases: sample database from catalyst and minimaybridge.
Results and Discussion: The best hit with good fit value and low predicted activity was further modified
to design novel drug-like molecules, which were able to bind to Squalene synthase enzyme active site.
Conclusion: The best scoring molecule, compound 67 showed 53% inhibition of the human Squalene
synthase enzyme, isolated from the cell lysates of Human Hepatoma Cell Line, at a dose of 10 mcg
with an IC50 value of 9.43 µm.