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

Content Provider	Springer Nature Link
Author	Qiao, Lian sheng Zhang, Xian bao Jiang, Lu di Zhang, Yan ling Li, Gong yu
Copyright Year	2016
Abstract	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.
Starting Page	933
Ending Page	944
Page Count	12
File Format	PDF
ISSN	13811991
Journal	Molecular Diversity
Volume Number	20
Issue Number	4
e-ISSN	1573501X
Language	English
Publisher	Springer International Publishing
Publisher Date	2016-06-21
Publisher Place	Cham
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	ACAT-2 Hyperlipidemia Pharmacophore SVM SVR Virtual screening Traditional Chinese medicine Biochemistry Organic Chemistry Polymer Sciences Pharmacy
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Medicine Drug Discovery Molecular Biology Physical and Theoretical Chemistry Information Systems Catalysis Inorganic Chemistry

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