Yan Wang1, Wei Qi2, Li Zhang3, Zhenguang Ying4, Ou Sha4, Chunman Li4, Lanhai Lü5, Xiangyan Chen6, Zhenzhong Li7, Feng Niu8, Fang Xue7, Dong Wang7, Tzi-Bun Ng1, Lihong Zhang7. 1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. 2. Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang 050000, China. 3. Department of Physiology and Neurology, University of Connecticut, Storrs 06269USA. 4. Department of Anatomy, Histology and Developmental Biology, School of Basic Medical Sciences, Shenzhen University Health Science Centre, Shenzhen 518060, China. 5. Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville 40202, USA. 6. Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. 7. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. 8. Central Institute of Pharmaceutical Research, Shijiazhuang Pharmaceutical Group Co., Ltd., Shijiazhuang 050035, China.
Abstract
BACKGROUND: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. METHODS: The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free. The software AutoDock Vina was used for all dockings. The binding targets of NBP were illustrated as 3-D and 2-D diagrams. RESULTS: Firstly, the results showed that NBP bounded to the same binding site on NAD(P)H quinone oxidoreductases (NQO1) as the substrate FAD, leading to competitive inhibition for the catalytic site with -7.2 kcal/mol. This might break the 3-D structure of NQO1 and bring about P53 degradation, resulting in a decrease of p53-mediated apoptosis in ischemic brain cells. Secondly, NBP might exert its therapeutic effect on acute ischemic stroke via modulating indoleamine 2,3-dioxygenase (IDO) bioactivity after associating with it. NBP could alleviate the depression following ischemic stroke by inhibiting IDO. Thirdly, NBP might modulate the function of NADH-ubiquinone oxidoreductase by competitively embedding itself into this complex, further affecting mitochondrial respiration in cerebrovascular diseases as an anti-oxidant agent. CONCLUSIONS: Three potential target proteins of NBP were identified, which may provide a novel aspect for better understanding the protective effects of NBP on the nervous system at the molecular level.
BACKGROUND: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. METHODS: The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free. The software AutoDock Vina was used for all dockings. The binding targets of NBP were illustrated as 3-D and 2-D diagrams. RESULTS: Firstly, the results showed that NBP bounded to the same binding site on NAD(P)H quinone oxidoreductases (NQO1) as the substrate FAD, leading to competitive inhibition for the catalytic site with -7.2 kcal/mol. This might break the 3-D structure of NQO1 and bring about P53 degradation, resulting in a decrease of p53-mediated apoptosis in ischemic brain cells. Secondly, NBP might exert its therapeutic effect on acute ischemic stroke via modulating indoleamine 2,3-dioxygenase (IDO) bioactivity after associating with it. NBP could alleviate the depression following ischemic stroke by inhibiting IDO. Thirdly, NBP might modulate the function of NADH-ubiquinone oxidoreductase by competitively embedding itself into this complex, further affecting mitochondrial respiration in cerebrovascular diseases as an anti-oxidant agent. CONCLUSIONS: Three potential target proteins of NBP were identified, which may provide a novel aspect for better understanding the protective effects of NBP on the nervous system at the molecular level.
Authors: Lihong Zhang; Wan-hua Amy Yu; Yi-Xiang J Wang; Chunmei Wang; Feng Zhao; Wei Qi; W M Chan; Yin Huang; Maria S M Wai; Jinghui Dong; D T Yew Journal: Curr Neurovasc Res Date: 2012-08 Impact factor: 1.990
Authors: Katherine A Jackman; Vanessa H Brait; Yutang Wang; Ghassan J Maghzal; Helen J Ball; Gavin McKenzie; T Michael De Silva; Roland Stocker; Christopher G Sobey Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2011-02-27 Impact factor: 3.000