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Type I methionine aminopeptidase from Saccharomyces cerevisiae is a potential target for antifungal drug screening

Acta Pharmacologica Sinica 2004年第7期25卷 61-68页

作者： Ling-ling CHEN, Jia LI, Jing-ya LI, Qun-li LUO, Wei-feng MAO, Qiang SHEN, Fa-jun NAN3, Qi-zhuang YE2,3 nationalCenter for drug Screening, Instituteof Materia Medica, Shanghai institutes for BiologicalSciences, Chinese AcademyofSciences, Shanghai 201203, china 2 The High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas 66047, USA national Center for drug Screening Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

AIM: To screen antifungal drug candidates using in vitro and in vivo assays based on type I methionine aminopep- tidase from Saccharomyces cerevisiae (ScMetAP1). METHODS: A colorimetric assay suitable for high throughput screening (HTS) using recombinant ScMetAP1 protein expressed in Escherichia coli was established for antifungal lead discovery. A series of pyridine-2-carboxylic acid derivatives were characterized and a chemical library of 12 800 pure organic compounds was screened with the in vitro ScMetAP1 assay. Active compounds from the in vitro assay were further evaluated by a growth inhibition assay on yeast strain with deletion of ScMetAP1 gene map1 in comparison with the wild-type yeast strain and the yeast strain with deletion of type II enzyme (ScMetAP2) gene map2. RESULTS: Active ScMetAP1 inhibitors were identified from HTS. Some of the pyridine-2-carboxylic acid derivatives (compound 2 and 3) had selective inhibition of the growth of map2 deletion yeast and weak inhibition on wild-type yeast growth, while no inhibition on map1 deletion yeast. CONCLUSION: ScMetAP1 is a novel potential target for developing antifungal drugs. The in vitro and in vivo ScMetAP1 assays can serve as tools in discovering antifungal drug candidates.

关键词： methionine aminopeptidase high-throughput screening antifungal agent

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Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to β-secretase

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Acta Pharmacologica Sinica 2006年第12期27卷 1586-1593页

作者： Bin HU Bing XIONG Bei-ying QIU Xin LI Hai-ping YU Kun XIAO Xin WANG Jia LI Jing-kang SHEN~2 State Key Laboratory of drug Research and national Center for drug Screening,Shanghai Institute of Materia Medica,Shanghai institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 201203,china State Key Laboratory of drug Research and national Center for drug Screening Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

Aim:To develop probes for detecting the binding specificity between β-secretaseand substrate,and provide reliable biological activity data for further researchingencircling substrate-based ***:To prepare the inhibitors,thehydroxyethylene(HE)segment including P1and P1′ was synthesized after multi-step reactions;the combination of all segments was then completed through solidphase *** human β-secretase ectodomain(amino acid resi-dues 1-460)was expressed as a secreted protein with a C-terminal His tag in insectcells using baculovirus infection,and all compounds were evaluated in thisβ-secretase enzyme *** order to understand the interaction in detail,the theoretical methods,namely molecular dynamics(MD)simulation and mo-lecular mechanics-generalized-born surface area(MM-GBSA)analysis,were per-formed on the complex of β-secretase and OM99-2 to obtain the geometrical andenergetical ***:We designed and constructed a positional scan-ning combinatorial library including 16 compounds;all members of the librarywere synthesized based on HE dipeptide ***-activity relationshipstudies at the P4-P1and P1′-P4′ positions led to the discoveries of P and P’sidesbinding specificity and potent inhibitors 14,18,and *** binding free energyon the whole system and every residue were compared to the biological ***:The removal of P4′ yielded inhibitor 22(A3*B2)with highpotency;further truncation of P3′ gave inhibitor 18(A3*B1)with equal activity,implying that the right side of the inhibitors play a less important role and could beeasily simplified,while change on the P side may cause substantial results.

关键词： β-secretase hydroxyethylene OM99-2 Alzheimer’s disease structure-activity relationship

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Phylogenetic origin of Beckmannia (Poaceae) inferred from molecular evidence

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Journal of Systematics and Evolution 2009年第4期47卷 305-310页

作者： ~(1,2)Chong-Mei XU ~3Chang-You QU ~(2,4)Wen-Guang YU ~2Xue-Jie ZHANG ~2Fa-Zeng LI~* 1(Weifang Medical University,Weifang 261053,china) 2(College of Life Sciences,Shandong Normal University,Jinan 250014,china) 3(Shandong drug and food Vocational College,Weihai 264400,china) 4(Shandong Shengli Co.Ltd.,Jinan 250101,china) ( Shandong Shengli Co. Ltd. Jinan 250101 China)

The phylogenetic origin of Beckmannia remains *** genus has been placed within the Chlorideae,Aveneae(Agrostideae),Poeae,or treated as an isolate lineage,*** the present study, we used nuclear internal transcribed spacer(ITS)and chloroplast trnL-F sequences to examine the phylogenetic relationship between Beckmannia and those genera that have assumed to be *** the basis of the results of our studies,the following conclusions could be drawn:(i)Beckmannia and Alopecurus are sister groups with high support;and(ii)Beckmannia and Alopecurus are nested in the Poeae clade with high *** results of our analysis suggest that Beckmannia should be placed in Poeae.

关键词： Aveneae Beckmannia internal transcribed spacer(ITS) phylogeny Poeae trnL-F.

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New Collection of Crude drugs in Chinese Pharmacopoeia 2010 Ⅰ.Callicarpa Linn. and Related Items

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Chinese Herbal Medicines 2010年第4期02卷 272-288页

作者： DAN Yang1, QIAN Zhong-zhi2, LIU Yan-ze1, ZHOU Guo-ping3, PENG Yong1, XIAO Pei-gen1 1. Institute of Medicinal Plant Development, Chinese Academy of Medical Science, beijing 100193, china 2. china Pharmacopoeia Committee, beijing 100061, china 3. Jiangxi Provincial Institute for food and drug control, Nanchang 330046, china Institute of Medicinal Plant Development Chinese Academy of Medical ScienceBeijing 100193China china Pharmacopoeia Committee Beijing 100061China Jiangxi Provincial Institute for food and drug control Nanchang 330046China

Callicarpa Linn. (beautyberry) is one of the major genera in Verbenaceae, about 20 of which are medicinal plants. Beautyberry, called Zizhu in china, is a generic name of those species and largely used as hemostatic medicine. The Chinese Pharmacopoeia 2010 has admitted three new crude drugs from the genus of Callicarpa Linn. including Callicarpae Macrophyllae Folium, Callicarpae Caulis et Folium, and Callicarpae Formosanae Folium for the first time since the 1977 version of the Chinese Pharmacopoeia. In order to better understand these new crude drugs, we systematically described their bibliography, admission reasons, botanical identification, chemistry, and pharmacology. Several other species, out of national regulations but intensively studied and widely used, are also covered in this review.

关键词： Callicarpa formosana Callicarpa kwangtungensis Callicarpa Linn. Callicarpa macrophylla Chinese patent medicine Chinese Pharmacopoeia quality assessment

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Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations

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Acta Pharmacologica Sinica 2004年第12期25卷 146-152页

作者： Xiao-hui CAI, Qing ZHANG, Da-fu DING2 Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, china Key Laboratory of Proteomics Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Graduate School of the Chinese Academy of Sciences Shanghai 200031 China

AIM: To model the three-dimensional structure and investigatethe interaction mechanism ofthe proprotein convertase furin/kexin and their inhibitors (eglin c mutants). METHODS: The three-dimensional complex structures of furin/ kexin with its inhibitors, eglin c mutants, were generated by modeller program using the newly published X-ray crystallographical structures of mouse furin and yeast kexin as templates. The electrostatic interaction energy of each complex was calculated and the results were compared with the experimentally determined inhibition con- stants to find the correlation between them. RESULTS: High quality models of furin/kexin-eglin c mutants were obtained and used for calculation of the electrostatic interaction energies between the proteases and their inhibitors. The calculated electrostaticenergies of interaction showeda linear correlation to the experimental inhibition constants. CONCLUSION: The modeled structures give good explanations of the specificity of eglin c mutants to furin/ kexin. The electrostatic interactions play important roles in inhibitory activity of eglin c mutants to furin/kexin. The results presented here provided quantitative structural and functional information concerning the role of the charge- charge interactions in the binding of furin/kexin and their inhibitors.

关键词： furin kexin eglin c drug design electrostatic mutation

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Pharmacophore-directed Homology Modeling and Molecular Dynamics Simulation of G Protein-coupled Receptor: Study of Possible Binding Modes of 5-HT2C Receptor Agonists

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Acta Biochimica et Biophysica Sinica 2007年第6期39卷 413-422页

作者： Chummok PUAH Centre for Biomedical & Life Sciences Singapore Polytechnic Singapore 13965

A new pharmacophore-based modeling procedure, including homology modeling, pharmacophore study, flexible molecular docking, and long-time molecular dynamics （MD） simulations, was employed to construct the structure of the human 5-HT2C receptor and determine the characteristics of binding modes of 5-HT2C receptor agonists. An agonist-receptor complex has been constructed based on homology modeling and a pharmacophore hypothesis model based on some high active compounds. Then MD simulations of the ligand-receptor complex in an explicit membrane environment were carried out. The conformation of the 5- HT2C receptor during MD simulation was explored, and the stable binding modes of the studied agonist were determined. Flexible molecular docking of several structurally diverse agonists of the human 5-HT2C receptor was carried out, and the general binding modes of these agonists were investigated. According to the models presented in this work and the results of Flexi-Dock, the involvement of the amino acid residues Asp134, Ser138, Ash210, Asn331, Tyr358, Ile131, Ser132, Val135, Thr139, Ile189, Val202, Val208, Leu209, Phe214, Val215, Gly218, Ser219, Phe223, Trp324, Phe327, and Phe328 in agonist recognition was studied. The obtained binding modes of the human 5-HT2C receptor agonists have good agreement with the site-directed mutagenesis data and other studies.

关键词： 5-HT2C receptor Flexi-Dock G protein-coupled receptor homology modeling molecular dynamics simulation

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Magnesium lithospermate B ameliorates renal cortical microperfusion in rats

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Acta Pharmacologica Sinica 2006年第2期27卷 217-222页

作者： Chun-guang CHEN~(2,3) Yi-ping WANG~(2,4) ~2State Key Laboratory of drug Research.Shanghai Institute of Materia Medica,Shanghai institutes for Biological Sciences Graduate School of the Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 201203,china StateKeyLaboratoryofdrugResearch ShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciences GraduateSchooloftheChineseAcademyofSciences ChineseAcademyofSciencesShanghai201203China

Aim:To investigate the effects of magnesium lithospermate B（MLB）isolatedfrom Salviae miltiorrhizae on renal microcirculation,and renal and systemic he-modynamics in Sprague-Dawley ***:MLB（10,30,and 60 mg/kg）wasinjected intravenously and renal blood flow（RBF）,renal cortical microperfusion（RCM）,and systemic hemodynamic function parameters including heart rate（HR）,mean arterial pressure（MAP）,left ventricular systolic pressure（LVSP）,left ven-tricular end-diastolic pressure（LVEDP）,and maximal velocity of pressure increase(dp/dtmax)were measured for 45 min after ***:IntravenousMLB at doses of 10,30,and 60 mg/kg increased RCM significantly,but had noobvious effects on RBF or systemic *** effect of MLB on RCMreached its peak 15 rain after injection and returned to baseline after 45 *** to60 mg/kg MLB increased RCM by 62.4%±20.2%（changes from baseline,P<0.01）,whereas RBF（3.7%±9.7% vs baseline）and renal vascular resistance（-1.4%±9.1%vs baseline）did not obviously ***:These results indicate thatMLB ameliorates renal microcirculation in a dose-dependent manner,which maybe related to the renoprotective effects of MLB.

关键词： magnesium lithospermate B hemodynamics renal blood flow renal cortical microperfusion

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UHPLC-MS/MS同时测定大鼠血浆中裸花紫珠3个酚苷类成分及其药动学研究

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中草药 2015年第23期46卷 3533-3538页

作者：郑东昆陈伟康马双成邵军王杰罗跃华江西省药品检验检测研究院/江西省药品与医疗器械质量工程技术研究中心江西南昌330029 南昌大学药学院江西南昌330006 中国食品药品检定研究院北京100050

目的建立超高效液相色谱-串联质谱法(UHPLC-MS/MS)同时测定大鼠血浆中毛蕊花糖苷、异毛蕊花糖苷及连翘酯苷B的水平,并计算3个酚苷类成分在大鼠体内的药动学参数。方法大鼠ig给予裸花紫珠提取物(5 g/kg)后不同时间取血浆,血浆样品经盐酸... 详细信息

目的建立超高效液相色谱-串联质谱法(UHPLC-MS/MS)同时测定大鼠血浆中毛蕊花糖苷、异毛蕊花糖苷及连翘酯苷B的水平,并计算3个酚苷类成分在大鼠体内的药动学参数。方法大鼠ig给予裸花紫珠提取物(5 g/kg)后不同时间取血浆,血浆样品经盐酸处理,乙腈沉淀蛋白后,以乙腈-0.005%甲酸为流动相,通过Phenomenex®Kinetex C18柱(50 mm×2.1 mm,1.7μm)梯度洗脱;采用电喷雾离子化源(ESI)三重四极杆串联质谱,以多反应监测模式(MRM)负离子测定血浆中毛蕊花糖苷、异毛蕊花糖苷、连翘酯苷B。结果毛蕊花糖苷、异毛蕊花糖苷、连翘酯苷B分别在7.77~3 880.00 ng/m L(r^2=0.995 5)、5.04~2 520.00 ng/m L(r^2=0.994 9)、1.78~890.00 ng/m L(r^2=0.995 1)呈良好的线性关系,各成分的提取回收率在75.2%~89.9%,日内、日间精密度RSD均小于8.8%。大鼠ig给予裸花紫珠提取物后,毛蕊花糖苷、异毛蕊花糖苷及连翘酯苷B均在30 min左右达到最大血药浓度,AUC0~t分别为(93 881.65±18 326.65)、(29 204.97±8 499.88)、(15 027.05±3 763.82)ng·min/m L,Cmax分别为(2 179.00±355.60)、(737.57±210.31)、(227.30±48.38)ng/m L,t1/2z分别为(235.41±117.90)、(151.56±49.23)、(161.68±63.92)min。结论建立的UHPLC-MS/MS方法简便、快速、专属性强,可用于大鼠血浆中毛蕊花糖苷、异毛蕊花糖苷、连翘酯苷B的同时测定及其药动学研究。

关键词：裸花紫珠毛蕊花糖苷异毛蕊花糖苷连翘酯苷B 超高效液相色谱-串联质谱法药动学

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Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells

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Acta Pharmacologica Sinica 2005年第6期26卷 673-678页

作者： Li-li TANG, Rui WANG, Xi-can TANG~2 State Key Laboratory of drug Research, Shanghai Institute of Materia Medica, Shanghai institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, china StateKeyLaboratoryofdrugResearch ShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesChineseAcademyofScienc

Aim: To study the effects of huperzine A (HupA) on neuritogenic activity and the expression of nerve growth factor (NGF). Methods: After being treated with 10 μmol/L HupA, neurite outgrowth of PC 12 cells was observed and counted under phase-contrast microscopy. Mitogenic activity was assayed by [~3H]thymidine incorporation. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. AChE activity, mRNA and protein expression were measured by the Ellman’s method, RT-PCR, and Western blot, respectively. NGF mRNA and protein levels were determined by RT-PCR and ELISA assays. Results: Treatment of PC 12 cells with 10 渭mol/L HupA for 48 h markedly increased the number of neurite-bearing cells, but caused no significant alteration in cell viability or other signs of cytotoxicity. In addition to inhibiting AChE activity, 10 渭mol/L HupA also increased the mRNA and protein levels of this enzyme. In addition, following 2 h exposure of the astrocytes to 10 渭mol/L HupA, there was a significant up-regula-tion of mRNA for NGF and P75 low-affinity NGF receptor. The protein level of NGF was also increased after 24 h treatment with HupA. Conclusion: Our findings demonstrate for the first time that HupA has a direct or indirect neurotrophic activity, which might be beneficial in treatment of neurodegenerative disorders such as Alzheimer disease.

关键词： huperzine A nerve growth factor neurite outgrowth: acetylcholinesterase inhibitors

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Identification of raw Cuscutae Semen and its processed products by high performance liquid chromatography/diode-array detection/mass spectrometry(HPLC-DAD-MS) combined with principle component analysis

Identification of raw Cuscutae Semen and its processed produ...

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中药与天然药高峰论坛暨第十二届全国中药和天然药物学术研讨会

作者： Xian-Long Cheng~(a,c,1),Li-Yuan Xu~(a,b,1),Feng Wei~(a,c),Ling Dong~a,Zhi-Meng Li~d,Xiang-Ri Li~(*a,b), Shuang-Cheng Ma~(*a,c),Rui-Chao Lin~(a,c) a School of Chinese Materia Medica,beijing University of Chinese Medicine,No.6 Wangjing Zhong Huan Nan Lu,Chaoyang District,beijing,100102,PR china b Research Center of CM Processing Technology,beijing University of Chinese Medicine,No.6 Wangjing Zhong Huan Nan Lu,Chaoyang District,beijing,100102,P.R china c Institute for control of Chinese Traditional Medicine and Ethnic Medicine, national institutes for food and drug control,State food and drug Administration,2 Tiantan Xili,beijing,100050,P.R china d Scientific Research Institute of beijing Tongrentang Pharmaceutical Company 20 Nansanhuan Zhong Lu,beijing,100079,PR china

In this study,The fingerprints of Cuscutae Semen and its processed products such as qing chao pin(QCP),jiu zhi pin(JZP)and yan zhi pin(YZP)were performed using hight performance liquid chromatography.10 chromatographic peaks were selected as characteristic peaks,the relative peak areas(RPA)of which were calculated for quantitative expression of the HPLC fingerprints. The RPA of 10 chromatographic peaks were subjected to principal component analysis(PCA)in order to classify raw Cuscutae Semen and its processed *** component analysis (PCA)of the analytical data showed that raw Cuscutae Semen and its processed products could be clustered reasonably into four different groups corresponding to different processed *** chemical markers of different samples given by the loadings plot of PCA were identified tentatively by electrospray ionization iontrap mass spectrometry and partially verified by the available reference *** results from this study indicate that the proposed method is reliable,and it has been successfully applied to the identification of raw Cuscutae Semen and its processed products used in Traditional Chinese Medicine(TCM)..

关键词： Cuscutae Semen processed products HPLC-DAD-MS PCA

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