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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 2.12.3,china 3 Division of Anti-tumor Pharmacology,shanghai institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences,shanghai 2.12.3,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

Protective effect of raloxifene on lipopolysaccharide and acid-induced acute lung injury in rats

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Acta Pharmacologica Sinica 2007年第10期28卷 1585-1590页

作者： Guang-ju ZHOU~1,Hong ZHANG~2,Sheng-de ZHI~3,Guo-ping JIANG~1,Jing WANG~2,Mao ZHANG~1,Jian-xin GAN~1,Shao-wenXU~1,Guan-yu JIANG~(1,4)~1 Department of Emergency Medicine,Second Affiliated Hospital,Zhejiang University,School of Medicine and Research institute of Emer-gency Medicine,Hangzhou 310009,china ~2 Department of Nuclear Medicine,Second Affiliated Hospital,Zhejiang University,Hangzhou310009,china ~3 drug design and discovery center,shanghai institute of materia medica,shanghai institute for biological sciences,chinese academy of sciences,shanghai 2.12.3,china Department of Emergency Medicine Second Affiliated Hospital Zhejiang University School of Medicine and Research Institute of Emergency Medicine Hangzhou China Department of Nuclear Medicine Second Affiliated Hospital Zhejiang University Hangzhou China drug design and discovery center Shanghai Institute of Materia Medica Shanghai Institute for Biological Sciences Chinese Academy of Sciences Shanghai China

Aim:To evaluate the protective effect of oral raloxifene on acute lung ***:Thirty adult,male Sprague-Dawley rats each weighing 180-210 g wereused and divided into 3 groups:the raloxifene-lipopolysaccharide （LPS）-HCl group（n=10）,the LPS-raloxifene-HCl group （n=10）,and the placebo group （n=10）.Allthe rats were injected intraperitoneally （ip） with 5 mg/kg LPS,and raloxifene （30mg/kg） was orally administered 1 h before and 14 h after LPS injection into theraloxifene-LPS-HCl and the LPS-raloxifene-HCl groups,respectively;the placebogroup received *** hours after LPS injection,all the animals wereanesthetized and the femoral artery was *** the rats received a directintratracheal （IT） injection of HCl（pH 1.2;0.5 mL/kg）.The mean arterial pressure（MAP） and blood gas concentrations were *** rats （5 in eachgroup,respectively） underwent a micro positron emission tomography （microPET）scan of the thorax 4 h after HCl *** wet/dry （W/D） weight ratiodetermination and histopathological examination were also ***:The rats in the LPS-raloxifene-HCl group had a lower [18F]fluorodeoxyglucoseuptake compared with the rats in the placebo group （4.67±1.33 vs 9.01±1.58,respectively,P3 vs 12.6±0.97,respectively,P335±0.198 vs 5.886±0.257,respectively,P<0.01） compared tothe placebo *** rats in this group also showed better pulmonary gasexchange and more stable mean arterial pressure （MAP） compared to the ***:Raloxifene provides a significant protective effect on acutelung injury in rats induced first by LPS ip injection and then by HCl IT instillation.

关键词： acute lung injury aspiration fluorodeoxyglucose lipopolysaccharide microPET pulmonary edema raloxifene

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

Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release

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Acta Pharmacologica Sinica 2005年第10期26卷 1201-1211页

作者： Hong-xia GUO~(2,3), Feng WANG~(2,3), Kun-qian YU~3, Jing CHEN~3, Dong-lu BAI~3, Kai-xian CHEN~3, Xu SHEN~(3,4,5), Hua-liang JIANG~(3,4,5) ~3 drug discovery and design center, State Key Laboratory of drug Research, shanghai institute of materia medica, shanghai institutes for Biologieal sciences Graduate School of the chinese academy of sciences, chinese academy of sciences, shanghai 2.12.3, china ~4 School of Pharmacy, East china University of Science and Technology shanghai 200237, china drug discovery and design center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Graduate School of the Chinese Academy of Sciences Shanghai 201203 China.

Aim: To investigate methods for identifying specific cyclophilin D （CypD） inhibitors derived from quinoxaline, thus developing possible lead compounds toinhibit mitochondrial permeability transition （MPT） pore opening. Methods: Kinetic analysis of the CypD/inhibitor interaction was quantitatively performed byusing surface plasmon resonance （SPR） and fluorescence titration （FT） ***50values of these inhibitors were determined by PPIase inhibition activity ***: All the equilibrium dissociation constants （KD） of the seven compoundsbinding to CypD were below 10 μmol/L. The IC50values were all consistent withthe SPR and FT results. Compounds GW2, 5, 6, and 7 had high inhibition activitiesagainst Ca2+-dependent rat liver mitochondrial swelling and Ca2+uptake/*** GW5 had binding selectivity for CypD over CypA. Conclusion: Theagreement between the measured IC50values and the results of SPR and FT suggests that these methods are appropriate and powerful methods for fyingCypD inhibitors. The compounds we screened using these methods （GW1-7） arereasonable CypD inhibitors. Its potent ability to inhibit mitochondrial swelling and the binding selectivity of GW5 indicates that GW5 could potentially be used for inhibiting MPT pore opening.

关键词： cyclophilin quinoxalines surface plasmon resonance mitochondrial permeability transition: fluorescence titration inhibitor

Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor

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Acta Pharmacologica Sinica 2006年第1期27卷 100-110页

作者： Gui-xia LIU~(2,3,4) Jin-zhi TAN~2 Chun-ying NIU~2 Jian-hua SHEN~(2,3) Xiao-min LUO~2 Xu SHEN~(2,3) Kai-xian CHEN~2 Hua-liang JIANG~(2,3,4)2 center for drug discovery and design,State Key Laboratory of drug Research,shanghai institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences,shanghai 2.12.3,china 3 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 Chinese Academy of Sciences Shanghai China School of Pharmacy East China University of Science and Technology Shanghai China

Aim:To investigate the dynamic properties of protein-tyrosine phosphatase (PTP)1B and reveal the structural factors responsible for the high inhibitory potencyand selectivity of the inhibitor SNA for ***:We performed moleculardynamics (MD) simulations using a long time-scale for both PTP1B and PTP1Bcomplexed with the inhibitor SNA,the most potent and selective PTP1B inhibitorreported to *** trajectories were analyzed by using principal ***:Trajectory analyses showed that upon binding the ligand,theflexibility of the entire PTP1B molecule *** most notable change is themovement of the *** simulation results also indicated that electro-static interactions contribute more to PTP 1B-SNA complex conformation than thevan der Waals interactions,and that Lys41,Arg47,and Asp48 play important rolesin determining the conformation of the inhibitor SNA and in the potency andselectivity of the *** these,Arg47 contributed *** results werein agreement with previous experimental ***:The informationpresented here suggests that potent and selective PTP1B inhibitors can be de-signed by targeting the surface residues,for example the region containing Lys41,Arg47,and Asp48,instead of the second phosphate binding site (besides theactive phosphate binding site).

关键词： molecular dynamics simulation principal component analysis protein-tyrosine phosphatase 1B type 2 diabetes

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 2.12.3,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

3D-QSAR study of 20(S)-camptothecin analogs

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Acta Pharmacologica Sinica 2007年第2期28卷 307-314页

作者： Ai-jun LU~(1,2) Zhen-shan ZHANG~2 Ming-yue ZHENG~2 Han-jun ZOU~2 Xiao-min LUO~2 Hua-liang JIANG~(2,3,4)1 Jiangsu Simcere Pharmaceutical Research Company Ltd,Nanjing 210042,china 2 drug discovery and design center,State Key Lab of drug Research,shanghai institute of materia medica,chinese academy of sciences,shanghai 2.12.3,china 3 School of Pharmacy,East china University of Science and Technology,shanghai 200237,china Jiangsu Simcere Pharmaceutical Research Company Ltd Nanjing China drug discovery and design center State Key Lab of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China School of Pharmacy East China University of Science and Technology Shanghai China

Aim:To build up a quantitative structure-activity relationship（QSAR）model of20（S）-camptothecin（CPT）analogs for the prediction of the activity of new CPTanalogs for drug ***:A training set of 43 structurally diverse CPTanalogs which were inhibitors of topoisomerase I were used to construct a quan-titative structure-activity relationship model with a comparative molecular fieldanalysis（CoMFA）.The QSAR model was optimized using partial least squares（PLS）analysis.A test set of 10 compounds was evaluated using the ***:The CoMFA model was constructed successfully,and a good cross-validated correlation was obtained in which q2was ***,the analysis ofthe non-cross-validated PLS model in which r2was 0.935 was built and permitteddemonstrations of high predictability for the activities of the 10 CPT analogs inthe test set selected in ***:The CoMFA model indicated thatbulky negative-charged group at position 9,10 and 11 of CPT would increaseactivity,but excessively increasing bulky group at position 10 is adverse to inhibi-tory activity;substituents that occupy position 7 with the bulky positive groupwill enhance the inhibitive *** model can be used to design new CPTanalogs and understand the mechanism of action.

关键词： comparative molecular field analysis(CoMFA) camptothecin(CPT) topoisomerase I(Top I)

design,synthesis and antitumor evaluation of a new series of N-substi-tuted-thiourea derivatives

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Acta Pharmacologica Sinica 2006年第9期27卷 1259-1271页

作者： Jian LI~2 Jin-zhi TAN~2 Li-li CHEN~2 Jian ZHANG~2 Xu SHEN~(2,3)Chang-lin MEI~(4,6)Li-li FU~4 Li-ping LIN~5 Jian DING~5 Bing XIONG~2 Xi-shan XIONG~4 Hong LIU~(2,6)Xiao-min LUO~(2,6)Hua-liang JIANG~(2,3)2 drug discovery and design Centre,State Key Laboratory of drug Research,shanghai institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences,shanghai 2.12.3.china 3 School of Pharmacy.East china University of Science and Technology,shanghai 200237,china 4 Division of Nephrology,Department of Internal Medicine,Changzheng Hospital,Second Military medical University,shanghai 200003,china 5 Division of Antitumor Pharmacology,shanghai institute of materia medica,shanghai 2.12.3.china drug discovery and design Centre State Key Laboratory of Drug Research 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 Division of Nephrology Department of Internal Medicine Changzheng Hospital Second Military Medical University Shanghai China Division of Antitumor Pharmacology Shanghai Institute of Materia Medica Shanghai China

Aim:To design and synthesize a novel class of protein tyrosine kinase inhibitors,featuring the N-(2-oxo-1,2-dihydroquinolin-3-yl-methyl)-thiourea ***:First,compounds 1 and 2 were identified using the virtual screeningapproach in conjunction with binding assay based on surface plasmon ***,3 regions of compounds 1 and 2 were selected for chemical *** compounds were characterized potent inhibitory activities toward thehuman lung adenocarcinoma cell line SPAC ***:Forty new compounds(1-2,3a-g,4a-w,and 5a-l)were designed,synthesized and *** com-pounds(1,3e,41,4w,5a,and 5b)were found to show promising inhibitory activityagainst the SPAC1 tumor cell *** inhibitory activity of compound 5aincreases approximately 10 times more than that of the original compound ***:This study provides a promising new template with potential antitu-mot activity.

关键词： N-substituted-thiourea derivatives antitumor SPAC1 tyrosine kinase inhibitor virtual screening

Discovering Potential drug Leads via Docking,Synthesis and Bioassay

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Discovering Potential Drug Leads via Docking,Synthesis and B...