Identification of potential ACAT-2 selective inhibitors using pharmacophore, SVM and SVR from Chinese herbs

详细信息    查看全文

• 作者：Lian-sheng Qiao ; Xian-bao Zhang ; Lu-di Jiang ; Yan-ling Zhang…
• 关键词：ACAT ; 2 ; Hyperlipidemia ; Pharmacophore ; SVM ; SVR ; Virtual screening ; Traditional Chinese medicine
• 刊名：Molecular Diversity
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：20
• 期：4
• 页码：933-944
• 全文大小：1,913 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Analytical Chemistry
  Polymer Sciences
  Organic Chemistry
  Pharmacy
  
• 出版者：Springer Netherlands
• ISSN：1573-501X
• 卷排序：20

文摘

Acyl-coenzyme A cholesterol acyltransferase (ACAT) plays an important role in maintaining cellular and organismal cholesterol homeostasis. Two types of ACAT isozymes with different functions exist in mammals, named ACAT-1 and ACAT-2. Numerous studies showed that ACAT-2 selective inhibitors are effective for the treatment of hypercholesterolemia and atherosclerosis. However, as a typical endoplasmic reticulum protein, ACAT-2 protein has not been purified and revealed, so combinatorial ligand-based methods might be the optimal strategy for discovering the ACAT-2 selective inhibitors. In this study, selective pharmacophore models of ACAT-1 inhibitors and ACAT-2 inhibitors were built, respectively. The optimal pharmacophore model for each subtype was identified and utilized as queries for the Traditional Chinese Medicine Database screening. A total of 180 potential ACAT-2 selective inhibitors were obtained, which were identified using an ACAT-2 pharmacophore and not by our ACAT-1 model. Selective SVM model and bioactive SVR model were generated for further identification of the obtained ACAT-2 inhibitors. Ten compounds were finally obtained with predicted inhibitory activities toward ACAT-2. Hydrogen bond acceptor, 2D autocorrelations, GETAWAY descriptors, and BCUT descriptors were identified as key structural features for selectivity and activity of ACAT-2 inhibitors. This study provides a reasonable ligand-based approach to discover potential ACAT-2 selective inhibitors from Chinese herbs, which could help in further screening and development of ACAT-2 selective inhibitors.