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Development of a quantitative,cell-based,high-content screening assay for epidermal growth factor receptor modulators

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Acta Pharmacologica Sinica 2007年第10期28卷 1698-1704页

作者： jue wang~2,xin xie~(2,3)~2 The national center for drug screening,shanghai institute of materia medica,chinese academy of sciences Graduate School of chinese academyof sciences shanghai 201203,China The national center for drug screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Graduate School of chinese academy of sciences Shanghai China

Aim:To develop a robust,cell-based,high-content screening （HCS） assay basedon receptor internalization for the identification of novel modulators of the epi-dermal growth factor receptor （EGFR）.Methods:Agonist-induced receptorinternalization is part of the signaling cascade of ***-taggedepidermal growth factor （EGF） was used to visualize the internalized receptor-ligand *** fluorescent intracellular spots were detected and mea-sured with an ArrayScan HCS *** that can competitively bind toEGFR or interfere with EGFR internalization process would result in a reducednumber and intensity of intracellular fluorescent *** assay was validated,optimized,and applied to a large-scale screening of a library containing 48 000synthetic ***:The competition between fluorescent EGF andunlabeled EGF reveals the IC50of unlabeled EGF is approximately 0.2 nmol/L,which is comparable with other published *** compounds with arelatively high degree of interference with EGFR internalization were *** of the compounds was proven to be agonist of the EGFR since it inducedphosphorylation of the receptor and extracellular signal-regulated protein ki-nase （ERK）.Conclusion:This automated,objective,and easy-to-use assay pro-vided abundant information,quantitative results,and demonstrated the potentialuse of HCS methods in searching membrane receptor modulators.

关键词： high-content screening epidermal growth factor receptor receptor internalization competitive binding

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Development of a complex scintillation proximity assay for highthroughput screening of PPAR7 modulators

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Acta Pharmacologica Sinica 2005年第3期26卷 339-344页

作者： Bin WU Jie GAO Ming-wei wang~2 The national center for drug screening,shanghai institute of materia medica,shanghai institutes for Biological sciences,chinese academy of sciences Graduate School of chinese academy of sciences,shanghai 201203,China The national center for drug screening Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Graduate School of chinese academy of sciences Shanghai China

Aim:To develop a complex high-throughput screening （HTS） assay based onscintillation proximity assay （SPA） technology for identification of novel peroxi-some proliferator-activated receptor gamma （PPARγ） ***:Full-length PPARγ and retinoid X receptor alpha （RXRα）,biotinylated PPAR responseelement （PPRE）,[3H]BRL49653 and streptavidin-coated FlashPlate or microbeadwere used to develop an HTS assay based on SPA ***‘ABCDE’method was validated against conventional hydroxyapatite （HA） assay and ap-plied to large-scale screening of 16 000 synthetic compounds and natural ***:（1） IC50values of positive control compounds （BRL49653 andtroglitazone） obtained from the‘ABCDE’method and HA assay were compa-rable and consistent with those reported elsewhere;（2） Approximately 178compounds,showing more than 70% competitive inhibition on BRL49653 bind-ing to PPARγ,were identified initially by the‘ABCDE’method （microbead）;（3）Secondary screening using FlashPlate and cross-reactivity studies with RARα,β,γ and RXRα,β,γ confirmed that 12 compounds possessed specific PPARγ bind-ing properties including 2 with IC50values less than 0.5 μmol/L and novel chemi-cal ***:The‘ABCDE’method using either FlashPlate ormicrobead,is a highly efficient,automatable,and robust tool to screen potentialPPARγ modulators in HTS *** application may be expanded to othernuclear receptors that form heterodimers upon activation.

关键词： peroxisome proliferator-activated receptor gamma retinoid X receptor alpha scintillation proximity assay high-throughput screening

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Development of a homogeneous calcium mobilization assay for high throughput screening of mas-related gene receptor agonists

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Acta Pharmacologica Sinica 2007年第1期28卷 125-131页

作者： Rui ZHANG Pang-ke YAN Cai-hong ZHOU Jia-yu LIAO Ming-wei wang~2 The national center for drug screening,shanghai institute of materia medica,chinese academy of sciences,shanghai 201203,China The national center for drug screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Aim:To develop homogeneous calcium mobilization assay for high-throughputscreening(HTS)of mas-related gene(Mrg)receptor ***:CHO-Klcells stably expressing the full-length MrgD receptor and a calcium-sensitive dyewere used to develop an HTS assay based on intracellular calcium *** was applied to large-scale screening of a library containing 8000 syntheticcompounds and natural product extracts,cAMP measurements were carried outto verify the bioactivities of the hits found by the calcium mobilization *** approaches were also employed in the identification of the MrgA1 recep-tor agonists following HTS of 16000 ***:EC50values of the positivecontrol compounds(μ-alanine for MrgD receptor and dynorphin A for MrgA1receptor)determined by the calcium mobilization assay were consistent with thosereported in the literature,and the Z’factors were 0.65 and 0.50 for MrgD andMrgA1 receptor assay,*** 31 compounds for the MrgD receptorand 48 compounds for the MrgA1 receptor showing20% of the maximal agonistactivities found in the controls were initially identified as *** screen-ing confirmed that 2 compounds for each receptor possessed specific *** cAMP level measurements indicated that the 2 confirmedhits displayed the functionality of the MrgD receptor ***:Aseries of validation studies demonstrated that the homogeneous calcium mobili-zation assay developed was highly efficient,amenable to automation and a robusttool to screen potential MrgD and MrgA1 receptor *** application maybe expanded to other G-protein coupled receptors that mobilize calcium influxupon activation.

关键词： mas-related gene receptor calcium mobilization assay high-throughput screening

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Rhodanine derivatives as novel peroxisome proliferator-activated receptor γ agonists

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Acta Pharmacologica Sinica 2007年第12期28卷 2033-2039页

作者： Qing LIU,Yue-yun ZHANG,Hui-li LU,Qun-yi LI,Cai-hong ZHOU,Ming-wei wang~2The national center,for drug screening,shanghai institute of materia medica,chinese academy of sciences,shanghai 201203,China The national center for drug screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Aim:To characterize the in vitro bioactivities of rhodanine derivatives as novelperoxisome proliferator-activated receptor (PPAR)γ modulators,based on a hit(SH00012671) identified during high-throughput screening (HTS) of a diversesynthetic compound library,and to preliminarily elucidate the structure-activityrelationship of this class of PPARγ ***:Full-length PPARγ andretinoid X receptor α(RXRα),biotinylated PPAR response element (PPRE),[~3H]BRL49653 (rosiglitazone),and streptavidin-coated FlashPlate or microbeadswere used to measure the receptor-binding properties of various compounds basedon the scintillation proximity assay (SPA) technology.A recombinant PPRE vec-tor was transiently cotransfected with PPARγ and RXRα plasmids into the Africangreen monkey kidney (CV-1) cells,and the effects of BRL49653 and test com-pounds on transcription mediated by PPARγ were determined by examining lu-ciferase (reporter) responses.3T3-L1 cells were employed to determine whetherthe compounds facilitated adipogenesis upon PPARγ ***:Of the16 000 samples screened with the SPA method,only 1 compound (SH00012671)displayed a similar binding affinity (Ki=186.7 nmol/L) to PPARγ as BRL49653,butit was inactive in the cell-based assays.A series of rhodanine derivatives weresynthesized based on the core structure of SH00012671 and 8 of them showedagonist activities in both cotransfection and pre-adipocyte differentiation *** reduce intrinsic cytotoxicities,the sulphur on the rhodanine was changed *** alteration led to a decrease in receptor-binding affinities while modi-fied analogues generally maintained agonist efficacies in the cell-based *** the analogues studied,compound 31 exhibited about 70% the efficacy exertedby BRL49653 in both cotransfection and pre-adipocyte differentiation ***:Through minor chemical modifications on the core structure of theinitial HTS hit,SH00012671 was transformed to possess both molecular (PPARγ

关键词： rhodanine derivatives peroxisome proliferator-activated receptor structure-activity relationship adipogenesis

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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 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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Structure-based drug design of a novel family of chalcones as PPARα agonists:virtual screening,synthesis,and biological activities in vitro

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Acta Pharmacologica Sinica 2007年第12期28卷 2040-2052页

作者： Xiang-hua LI~(2,3),Han-jun ZOU~(2,3),An-hui WU~2,Yang-liang YE~2,Jian-hua SHEN~(2,4)~2 drug Discovery and Design center,State Key Laboratory of drug Research,shanghai institute of materia medica,chinese academy ofsciences,shanghai 201203,China drug Discovery and Design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Aim:To design and synthesize a novel class of peroxisome proliferator-activatedreceptors (PPAR)α agonists,which is obtained by the combination of the classi-cal fibrate"head group",a linker with appropriate length and a ***:Thirty seven compounds were designed and identified employing the virtualscreening *** compounds were then selected for synthesis and bioas-say according to the virtual screening results,structural similarity,and ***:Six new compounds (4b and 4d-h) were synthesized *** were found to be potent PPARα agonists,compound 4 h being themost prominent with a 50% effective concentration value of 0.06 μmol/***:This study provides a promising novel family of chalcones with a potentialhypolipidemic effect.

关键词： peroxisome proliferator-activated receptors drug design virtual screening

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Design,synthesis,antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives

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Acta Pharmacologica Sinica 2007年第1期28卷 140-152页

作者： Hai-hong LI~2 Xiu-hua ZHANG~3 Jin-zhi TAN~2 Li-li CHEN~2 Hong LIU~(2,5) Xiao-min LUO~(2,5) Xu SHEN~(2,4) Li-ping LIN~(3,5) Kai-xian CHEN~2 Jian DING~3 Hua-liang JIANG~(2,4)2 center for drug Discovery and Design,State Key Laboratory of drug Research,shanghai institute of materia medica,shanghai institutes for Biological sciences,and Graduate School,chinese academy of sciences,shanghai 201203,China 3 Division of Anti-tumor Pharmacology,shanghai institute of materia medica,shanghai institutes for Biological sciences,chinese academy of sciences,shanghai 201203,China 4 School of Pharmacy,East China University of Science and Technology,shanghai 200237,China center for drug Discovery and Design State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences and Graduate School Chinese Academy of Sciences Shanghai China Division of Anti-tumor Pharmacology Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China School of Pharmacy East China University of Science and Technology Shanghai China

Aim:To design and synthesize a novel class of antitumor agents,featuring the 3,5-substituted indolin-2-one ***:Based on enzyme binding fea-tures of（Z）-SU5402,introducing a β-pyrrole group at the 3-position of the indolin-2-one core,a series of novel 3,5-substituted indolin-2-ones were designed *** human carcinoma cell lines of A-43l,A-549,MDA-MB-468,and Autosomal Dominant Polycystic Kidney disease were chosen for the cellproliferation ***:Twenty new compounds（1a-t）with E configurationhave been designed,synthesized and *** structural features weredetermined by nuclear magnetic resonance（NMR）spectra,low-and high-resolu-tion mass spectra,and confirmed by X-ray *** the enzymeassay showed a weak inhibition effect against the epidermal growth factor receptor,vascular endothelial growth factor receptor,fibroblast growth factor receptor andplatelet-derived growth factor receptor tyrosine kinases,the cell-based antitumoractivity was *** 1 g and lh showed higher inhibitory activitytoward the A-549 and MDA-MB-468 cell lines with IC50of 0.065-9.4 μmol/***:This study provides a new template for further development ofpotent antitumor drugs.

关键词： protein-tyrosine kinase indolin-2-one antitumor drug screening assays drug design molecular models

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Metalloform-selective inhibition:Synthesis and structure-activity analysis of Mn（Ⅱ）-form-selective inhibitors of *** methionine aminopeptidase

Metalloform-selective inhibition:Synthesis and structure-act...

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中国化学会第四届有机化学学术会议

作者： Qing-Qing Huang, Min Huang, Qi-Zhuang Ye, Fa-Jun Nan chinese national center for drug screening, shanghai institute of materia medica, shanghai institutes for Biological sciences, 189 Guo-Shou-Jing Road, shanghai 201203, China The High Throughput screening Laboratory, University of Kansas, 1501Wakarusa Dr., Lawrence, KS 66047, USA

＜正＞Methionine aminopeptidase （MetAP） is a promising target for development of novel antibacterial, antifungal and anticancer agents. However, its physiologically relevant metal ion remains to be defined, and its inhibitors need to inhibit the in vivo metalloform. By high throughput screening of a chemical library of 43,736 small organic compounds,

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Design,synthesis,and evaluation of a biotinylated photoaffinity probe for labeling functional GABAB receptors on living cells

Design,synthesis,and evaluation of a biotinylated photoaffin...

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中国药理学会第十次全国学术会议

作者： xin Lin,Ming Jiang,xin Li,Fa-Jun Nan,Jian-Feng Liu (Key Laboratory of Molecular Biophysics of Ministry of Education,School of Life Science and Technology,Huazhong UniVersity of Science and Technology,1037 Luo Yu Road,Wuhan,Hubei,China,430074 national center for drug screening,State Key Laboratory of drug Research,shanghai institute of materia medica,shanghai institutes of Biological sciences, chinese academy of sciences,189 Guo Shou Jing Road,shanghai 201203,China)

γ-amidobutyric acid(GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system,exerts its effects through both ionotropic(GABA) and metabotropic(GABA) *** receptors mediate both presynaptic inhibition of neurotransmitter release and post-synaptic inhibition of neuronal excitability. Functional GABA receptor is composed of GABA and GABA subunits,each of which is unable to form a functional GABAB receptor in its own *** the qualitative analysis of functional GABA receptors on living cells,we have designed an activity-based photoaffinity biotinlyted probe based on CGP64213,a GABA selective high-affinity *** probe labels the functional GABA receptor on the cell surface with high specificity in the activity *** probe not only specifically binds GABA which heterodimerizes with GABA to form the functional GABAB receptor,but also indirectly fished out the GABAB2 which also form the functional GABAB receptor with *** results,therefore revealed that the feasibility of the probe we designed as a tool to qualitatively detect functional GABA receptor,as well as other important signal protein which interact with functional GABA receptor in living cells.

关键词： GABAB Receptor biotinlyted probe photoaffenity labeling

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Synthesis and PTP1B Inhibitory Evaluation of 2-naphthol tyrosine derivatives

Synthesis and PTP1B Inhibitory Evaluation of 2-naphthol tyro...

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2011年全国药物化学学术会议——药物的源头创新

作者： Liang-Peng Sun a,Qiang Shen b,Jia Li b,Hu-Ri Piao a,~* a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules,Ministry of Education,Yanbian University College of Pharmacy,Yanji,133000,PR China b national center for drug screening,shanghai institute of materia medica,shanghai institutes for Biological Science,chinese academy of sciences,shanghai 201203,China

＜正＞In recent years,a great attention are being payed to protein tyrosine phosphatase 1B（PTP1B） due to its pivotal role in type 2 diabetes and obesity as a negative regulator of the insulin and leptin-signaling pathway[1-2].Therefore,the search for potent small molecule protein tyrosine phosphatase 1B inhibitors is a major thrust area in the management of type 2 diabetes mellitus.

关键词： Protein tyrosine phosphatase 1B(PTP1B) Inhibitor Synthesis

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