Title:Pharmacophore-based Screening for Identification of Human Acyl-CoA Cholesterol Acyltransferase Inhibitors: An In-silico Study
Volume: 18
Issue: 8
Author(s): Ankit Dhaundiyal*, Puja Kumari and Shasta Kalra*
Affiliation:
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab,India
- Department of Zoology, College of Basic and Applied Sciences, Punjab Agricultural University, Ludhiana,India
Keywords:
Hypercholesterolemia, ACAT, pharmacophore, virtual screening, ADMET, PCA.
Abstract:
Aims: A pharmacophore based in silico study for screening out Human Acyl-CoA cholesterol
acyltransferase (ACAT) inhibitors.
Background: Human Acyl-CoA cholesterol acyltransferase (ACAT) plays an important role in catalysis
of reaction which converts cholesterol into cholesteryl esters and long-chain fatty acyl coenzyme
A. The inhibition of ACAT has therapeutically potential roles in hypercholestrolemia, atherosclerosis
and coronary heart disease.
Objective: As no 3D structure of Human Acyl-CoA cholesterol acyltransferase (ACAT) is reported,
ligand based design of the inhibitors is required that which converts cholesterol into cholesteryl esters.
Methods: For better understanding of essential chemical features for ACAT inhibition and identifying
novel inhibitors, a three-dimensional (3D) chemical-feature-based quantitative QSAR pharmacophore
model for available ACAT inhibitors have been developed for first time using Discovery Studio 2.5.
Results: The best model (Hypo1) having lowest total cost (84.14), highest cost difference (69.67),
highest correlation coefficient (0.94), and lowest RMS (1.15Å), constitutes of one hydrogen bond
acceptor, one hydrogen bond donor, two hydrophobic aromatic and one hydrophobic aliphatic feature.
The pharmacokinetic properties and toxicities of top 10 active hits obtained from virtual screening
were predicted for ZINC33073636 and ZINC33073625.
Conclusion: These studies thus provide a pharmacophore model, which will be helpful in designing
novel human ACAT inhibitors.
