Computational Discovery of Potential Acyl-CoA: Cholesterol Acyltransferase Inhibitors Using Structure-Based Virtual Screening

Abstract

Hyperlipidemia is a major metabolic disorder characterized by elevated levels of plasma lipids, including cholesterol and triglycerides, which contribute significantly to the development of atherosclerosis and subsequent cardiovascular complications such as angina pectoris, myocardial infarction, and cardiac arrest. Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme involved in intracellular cholesterol esterification, and its inhibition represents a promising therapeutic strategy for the management of hyperlipidemia. In the present study, molecular modeling approaches were employed to identify novel ACAT inhibitors with potential antihyperlipidemic activity. Pharmacophore models were developed based on structurally diverse, known ACAT inhibitors to elucidate essential molecular features governing enzyme inhibition. Following an extensive literature survey, a focused virtual library of heterocyclic compounds was designed to explore alternative lipid-lowering targets and to determine whether the observed hypolipidemic effects could be attributed to ACAT inhibition. Heterocyclic scaffolds, comprising ring systems containing atoms of at least two distinct elements, are known to play a pivotal role in drug discovery due to their versatile biological activities. Representative heterocycles such as quinoline, benzothiophene, indole, benzofuran, benzothiazole, benzimidazole, and benzoxazole were considered as structural templates for pharmacophore development. Among these, benzoxazole and benzothiazole moieties were selected as key pharmacophoric cores for the design of novel derivatives. These compounds were subjected to in silico screening using molecular docking and related computational techniques to assess their interaction with the ACAT active site.Several designed derivatives demonstrated favorable docking scores and strong binding affinities toward the ACAT receptor, indicating potential inhibitory activity. These promising heterocyclic compounds will be further evaluated through advanced computational studies and experimental assays to identify lead candidates for the development of novel antihyperlipidemic agents targeting ACAT.