Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore-Based Virtual Screening, Synthesis and Pharmacology

Abstract

The present study describes ligand-based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r=0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross-validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds (47 and 48; predicted IC 50=1nm) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10μg/mL) with IC 50 value of 3.6 and 2.5nm, respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors. A ligand-based pharmacophore modeling of a series of structurally diverse acyl CoA cholesterol acyltransferase (ACAT) inhibitors was carried out. Two most potent compounds (47 and 48; predicted IC 50=1nm) of the retrieved hits from virtual screening were synthesized and biologically evaluated. The results demonstrated that these compounds showed 86% and 88% inhibition of ACAT (at 10μg/mL) with IC 50 value of 3.6 and 2.5nm, respectively. © 2012 John Wiley & Sons A/S.