title: Identification of potential ACAT-2 selective inhibitors using pharmacophore, SVM and SVR from Chinese herbs.
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.
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Qiao
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
authors.forename: Xian-Bao
authors.initials: XB
authors.lastname: Zhang
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
authors.forename: Lu-di
authors.initials: LD
authors.lastname: Jiang
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing, 100102, China. collean_zhang@163.com.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
authors.forename: Gong-Yu
authors.initials: GY
authors.lastname: Li
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D060388:Support Vector Machine; D000097587:Sterol O-Acyltransferase 2
chemical_list: D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2
keywords: ACAT-2; Hyperlipidemia; Pharmacophore; SVM; SVR; Traditional Chinese medicine; Virtual screening