Pharmacophore-based screening for identification of human acyl-CoA cholesterol acyltransferase inhibitors: An in-silico study
A Dhaundiyal, P Kumari, S Kalra - Letters in Drug Design & …, 2021 - ingentaconnect.com
A Dhaundiyal, P Kumari, S Kalra
Letters in Drug Design & Discovery, 2021•ingentaconnect.comAims: 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 …
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 …
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.
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