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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 ResearchShanghai Institute of Materia MedicaChinese Academy oj SciencesShanghai 201203China

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 201203.china 3 School of Pharmacy,East china University of Science and Technology,shanghai 200237,china Jiangsu Simcere Pharmaceutical research Company Ltd Nanjing 210042ChinaDrug Discovery and Design CenterState Key Lab of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

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,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 centerfordrugdiscoveryanddesign StateKeyLaboratoryofDrugResearchShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesandGraduateSchoolChineseAcademyofSciencesShanghai201203China

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

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 201203.china 3 School of Pharmacy,East china University of Science and Technology shanghai 200237,china centerfordrugdiscoveryanddesign StateKeyLaboratoryofDrugResearchShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesChineseAcademyofSciencesShanghai201203China

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

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 201203, china ~4 School of Pharmacy, East china University of Science and Technology shanghai 200237, china drugdiscoveryanddesigncenter StateKeyLaboratoryofDrugResearchShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesGraduateSchooloftheChineseAcademyofSciencesChineseAcademyofSciencesShanghai

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

Swietenia mahagony extract shows agonistic activity to PPAR7 and gives ameliorative effects on diabetic db/db mice

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Acta Pharmacologica Sinica 2005年第2期 220-222页

作者： Dan-dan LI~(1,2,5),Jun-hua CHEN~(1,4,5),Qing CHEN~(1,4),Guo-wei LI~(1,4),Jing CHEN~(1,4),Jian-min YUE~(1,4),Min-li CHEN~3,Xiao-ping WANG~2,Jian-hua SHEN~(1,4,6),Xu SHEN~(1,4,6),Hua-liang JIANG~(1,4,6)~1drug discovery and design center,state key lab of drug research,shanghai institute of materia medica,shanghai institutes for Biologicalsciences,chinese academy of sciences,shanghai 201203,~2Chemistry Department,Tongji University,shanghai 200092,~3Animal Experi-ment center,Zhejiang College of Traditional chinese Medicine,Hangzhou 310053 ~4Graduate School of the chinese academy of sciences,china

Aim:To search the peroxisome proliferator-activated receptor γ(PPARγ)agonistsfrom Swietenia mahagony extract(SmE)and observe the possible ameliorativeeffects of SmE on diabetic db/db ***:The PPARγagonistic activity ofSmE was screened by yeast-two hybrid *** blood glucose levels ofdiabetic db/db mice were measured using a blood glucose level monitor and thedata were statistically analyzed by NDST8.8W ***:By using theclinical drug rosiglitazone as a positive control,it was found that the PPARγagonistic activity of SmE at a concentration of 50μg/L was approximately half thatof 35.7μg/L(0.1μmol/L)of *** the dose of 1000 mg/kg,SmE remark-ably decreased the blood glucose concentration of db/db mice from(15.26±2.98)to(7.58±2.20)mmol/L,and reduced the blood glucose levels by 55.49% comparedwith the control group(P<0.01).Conclusion:SmE shows agonistic activity toPPARγ and can ameliorate the blood glucose levels of diabetic db/db *** be thus used as a potential agent for diabetes therapy.

关键词： Swietenia mahagony diabetes mellitus peroxisome proliferator-activated receptor γ yeast-two hybrid

SPR technology and CD spectra in interaction between PPARγ-LBD and LigandsSPR technology and CD spectra in interaction between PPARγ-LBD and Ligands

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SPR technology and CD spectra in interaction between PPARγ-...

Thiosemicarbazones derivatives design,synthesis and their anti-cancer activity study

华东六省一市生物化学与分子生物学会2003年学术交流会

作者： Chang-ying Yu, Lili Chen, Feng Cheng, Rui-hao Zhang, Jian-hua Shen, Hua-liang Jiang, Xu Shen ( drug discovery and design center, state key laboratory of drug research, shanghai institute of materia medica, shanghai institutes for Biological sciences, chinese academy of sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, shanghai 201203, china)

PPAHγis a ligand-dependent transcription factor. It plays an important role in the regulation of adipocytefunction and systemic lipid homeostasis. PPARγparticipates in the biological pathways of basic and clinical inter-est,such as insulin sensitivity, type 2 diabetes and therosclerosis. In this report, the ligand binding characteristicsof a series of commercially available PPARγligands (GW9662, GI 262570, CPA, 15-d-PGJ, LY171883, Indom-ethacin, Linoleic acid, Palmitic acid and Troglitazone) to human PPARγligand-binding domain (LBD) were in-vestigated hy surface plasmon resonance biosensor (SPR) technology BIAcore 3000 and circular dichroism (CD)

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Thiosemicarbazones derivatives design,synthesis and their an...