publication . Article . Other literature type . 2018

Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect

Chen, Yankun; Chen, Xi; Luo, Ganggang; Zhang, Xu; Lu, Fang; Qiao, Liansheng; He, Wenjing; Li, Gongyu; Zhang, Yanling;
Open Access English
  • Published: 28 Apr 2018 Journal: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, volume 23, issue 5 (eissn: 1420-3049, Copyright policy)
  • Publisher: MDPI
Abstract
Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interacti...
Subjects
free text keywords: Article, hyperlipidemia, squalene synthase (SQS), molecular modeling, drug discovery, Traditional Chinese Medicine, Organic Chemistry, Squalene, chemistry.chemical_compound, chemistry, Biochemistry, Pharmacophore, Virtual screening, Cholesterol, Docking (molecular), Enzyme, chemistry.chemical_classification, In vitro
Related Organizations
63 references, page 1 of 5

Klop, B., Elte, J.W.F., Cabezas, M.C.. Dyslipidemia in obesity: Mechanisms and potential targets. Nutrients. 2013; 5: 1218-1240 [OpenAIRE] [PubMed] [DOI]

Maxfield, F.R., Tabas, I.. Role of cholesterol and lipid organization in disease. Nature. 2005; 438: 612-621 [OpenAIRE] [PubMed] [DOI]

Masters, B.A., Palmoski, M.J., Flint, O.P., Gregg, R.E., Wangiverson, D., Durham, S.K.. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol. Appl. Pharmacol.. 1995; 131: 163-174 [OpenAIRE] [PubMed] [DOI]

Ichikawa, M., Ohtsuka, M., Ohki, H., Ota, M., Haginoya, N., Itoh, M., Shibata, Y., Ishigai, Y., Terayama, K., Kanda, A.. Discovery of DF-461, a potent squalene synthase inhibitor. ACS Med. Chem. Lett.. 2013; 4: 932-936 [OpenAIRE] [PubMed] [DOI]

Davidson, M.H.. Squalene synthase inhibition: A novel target for the management of dyslipidemia. Curr. Atheroscler. Rep.. 2007; 9: 78-80 [OpenAIRE] [PubMed] [DOI]

Ichikawa, M., Ohtsuka, M., Ohki, H., Haginoya, N., Itoh, M., Sugita, K., Usui, H., Suzuki, M., Terayama, K., Kanda, A.. Discovery of novel tricyclic compounds as squalene synthase inhibitors. Bioorg. Med. Chem.. 2012; 20: 3072-3093 [OpenAIRE] [PubMed] [DOI]

Brusselmans, K., Timmermans, L., Van, D.S.T., Van Veldhoven, P.P., Guan, G., Shechter, I., Claessens, F., Verhoeven, G., Swinnen, J.V.. Squalene synthase, a determinant of raft-associated cholesterol and modulator of cancer cell proliferation. J. Biol. Chem.. 2007; 282: 18777-18785 [OpenAIRE] [PubMed] [DOI]

Warchol, I., Gora, M., Wysocka-Kapcinska, M., Komaszylo, J., Swiezewska, E., Sojka, M., Danikiewicz, W., Plochocka, D., Maciejak, A., Tulacz, D.. Genetic engineering and molecular characterization of yeast strain expressing hybrid human-yeast squalene synthase as a tool for anti-cholesterol drug assessment. J. Appl. Microbiol.. 2016; 120: 877 [OpenAIRE] [PubMed] [DOI]

Xie, W., Zhao, Y., Du, L.. Emerging approaches of traditional chinese medicine formulas for the treatment of hyperlipidemia. J. Ethnopharmacol.. 2012; 140: 345-367 [OpenAIRE] [PubMed] [DOI]

Rong, Q., Jiang, D., Chen, Y., Shen, Y., Yuan, Q., Lin, H., Zha, L., Zhang, Y., Huang, L.. Molecular cloning and functional analysis of squalene synthase 2 (SQS2) insalvia miltiorrhizabunge. Front. Plant Sci.. 2016; 7: 1274 [OpenAIRE] [PubMed] [DOI]

Zhan, D., Zhang, Y., Song, Y., Sun, H., Li, Z., Han, W., Liu, J.. Computational studies of squalene synthase from panax ginseng: Homology modeling, docking study and virtual screening for a new inhibitor. J. Theor. Comput. Chem.. 2012; 11: 1101-1120 [DOI]

Wang, X., Ren, Z., He, Y., Xiang, Y., Zhang, Y., Qiao, Y.. A combination of pharmacophore modeling, molecular docking and virtual screening for inos inhibitors from chinese herbs. Bio. Med. Mater. Eng.. 2014; 24: 1315-1322

Jiang, L., He, Y., Luo, G., Yang, Y., Li, G., Zhang, Y.. Discovery of potential novel microsomal triglyceride transfer protein inhibitors via virtual screening of pharmacophore modelling and molecular docking. Mol. Simul.. 2016; 42: 1223-1323 [OpenAIRE] [DOI]

Stein, E.A., Bays, H., O’Brien, D., Pedicano, J., Piper, E., Spezzi, A.. Lapaquistat acetate: Development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011; 123: 1974-1985 [PubMed] [DOI]

Hou, M., Yan, G., Ma, X., Luo, J., Hou, X., Zhou, M., Pu, C., Han, X., Zhang, W., Zhang, M.. Identification of hit compounds for squalene synthase: Three-dimensional quantitative structure-activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation. J. Chemom.. 2017; 31: e2923 [OpenAIRE] [DOI]

63 references, page 1 of 5
Abstract
Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interacti...
Subjects
free text keywords: Article, hyperlipidemia, squalene synthase (SQS), molecular modeling, drug discovery, Traditional Chinese Medicine, Organic Chemistry, Squalene, chemistry.chemical_compound, chemistry, Biochemistry, Pharmacophore, Virtual screening, Cholesterol, Docking (molecular), Enzyme, chemistry.chemical_classification, In vitro
Related Organizations
63 references, page 1 of 5

Klop, B., Elte, J.W.F., Cabezas, M.C.. Dyslipidemia in obesity: Mechanisms and potential targets. Nutrients. 2013; 5: 1218-1240 [OpenAIRE] [PubMed] [DOI]

Maxfield, F.R., Tabas, I.. Role of cholesterol and lipid organization in disease. Nature. 2005; 438: 612-621 [OpenAIRE] [PubMed] [DOI]

Masters, B.A., Palmoski, M.J., Flint, O.P., Gregg, R.E., Wangiverson, D., Durham, S.K.. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol. Appl. Pharmacol.. 1995; 131: 163-174 [OpenAIRE] [PubMed] [DOI]

Ichikawa, M., Ohtsuka, M., Ohki, H., Ota, M., Haginoya, N., Itoh, M., Shibata, Y., Ishigai, Y., Terayama, K., Kanda, A.. Discovery of DF-461, a potent squalene synthase inhibitor. ACS Med. Chem. Lett.. 2013; 4: 932-936 [OpenAIRE] [PubMed] [DOI]

Davidson, M.H.. Squalene synthase inhibition: A novel target for the management of dyslipidemia. Curr. Atheroscler. Rep.. 2007; 9: 78-80 [OpenAIRE] [PubMed] [DOI]

Ichikawa, M., Ohtsuka, M., Ohki, H., Haginoya, N., Itoh, M., Sugita, K., Usui, H., Suzuki, M., Terayama, K., Kanda, A.. Discovery of novel tricyclic compounds as squalene synthase inhibitors. Bioorg. Med. Chem.. 2012; 20: 3072-3093 [OpenAIRE] [PubMed] [DOI]

Brusselmans, K., Timmermans, L., Van, D.S.T., Van Veldhoven, P.P., Guan, G., Shechter, I., Claessens, F., Verhoeven, G., Swinnen, J.V.. Squalene synthase, a determinant of raft-associated cholesterol and modulator of cancer cell proliferation. J. Biol. Chem.. 2007; 282: 18777-18785 [OpenAIRE] [PubMed] [DOI]

Warchol, I., Gora, M., Wysocka-Kapcinska, M., Komaszylo, J., Swiezewska, E., Sojka, M., Danikiewicz, W., Plochocka, D., Maciejak, A., Tulacz, D.. Genetic engineering and molecular characterization of yeast strain expressing hybrid human-yeast squalene synthase as a tool for anti-cholesterol drug assessment. J. Appl. Microbiol.. 2016; 120: 877 [OpenAIRE] [PubMed] [DOI]

Xie, W., Zhao, Y., Du, L.. Emerging approaches of traditional chinese medicine formulas for the treatment of hyperlipidemia. J. Ethnopharmacol.. 2012; 140: 345-367 [OpenAIRE] [PubMed] [DOI]

Rong, Q., Jiang, D., Chen, Y., Shen, Y., Yuan, Q., Lin, H., Zha, L., Zhang, Y., Huang, L.. Molecular cloning and functional analysis of squalene synthase 2 (SQS2) insalvia miltiorrhizabunge. Front. Plant Sci.. 2016; 7: 1274 [OpenAIRE] [PubMed] [DOI]

Zhan, D., Zhang, Y., Song, Y., Sun, H., Li, Z., Han, W., Liu, J.. Computational studies of squalene synthase from panax ginseng: Homology modeling, docking study and virtual screening for a new inhibitor. J. Theor. Comput. Chem.. 2012; 11: 1101-1120 [DOI]

Wang, X., Ren, Z., He, Y., Xiang, Y., Zhang, Y., Qiao, Y.. A combination of pharmacophore modeling, molecular docking and virtual screening for inos inhibitors from chinese herbs. Bio. Med. Mater. Eng.. 2014; 24: 1315-1322

Jiang, L., He, Y., Luo, G., Yang, Y., Li, G., Zhang, Y.. Discovery of potential novel microsomal triglyceride transfer protein inhibitors via virtual screening of pharmacophore modelling and molecular docking. Mol. Simul.. 2016; 42: 1223-1323 [OpenAIRE] [DOI]

Stein, E.A., Bays, H., O’Brien, D., Pedicano, J., Piper, E., Spezzi, A.. Lapaquistat acetate: Development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011; 123: 1974-1985 [PubMed] [DOI]

Hou, M., Yan, G., Ma, X., Luo, J., Hou, X., Zhou, M., Pu, C., Han, X., Zhang, W., Zhang, M.. Identification of hit compounds for squalene synthase: Three-dimensional quantitative structure-activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation. J. Chemom.. 2017; 31: e2923 [OpenAIRE] [DOI]

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publication . Article . Other literature type . 2018

Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect

Chen, Yankun; Chen, Xi; Luo, Ganggang; Zhang, Xu; Lu, Fang; Qiao, Liansheng; He, Wenjing; Li, Gongyu; Zhang, Yanling;