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Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Acta Pharmacologica Sinica 2007年第12期28卷 2053-2063页

作者： Liang-liang SHEN,Gui-xia LIU,Yun TANG~2Laboratory of Molecular Modeling and Design,school of pharmacy,east china university of science and technology,shanghai 20023.,china Laboratory of Molecular Modeling and Design School of Pharmacy East China University of Science and Technology Shanghai China

Aim:To explore the binding mode of 2-substituted 1-indanone derivatives withacetylcholinesterase (AChE) and provide hints for the future design of new de-rivatives with higher potency and ***:The GOLD-docking con-formations of the compounds in the active site of the enzyme were used in subse-quent *** highly reliable and predictive three-dimensional quantitativestructure-activity relationship (3D-QSAR) models were achieved by comparativemolecular field analysis (CoMFA) and comparative molecular similarity analysis(CoMSIA) *** predictive capabilities of the models were validated byan external test ***,the stabilities of the 3D-QSAR models were veri-fied by the leave-4-out cross-validation ***:The CoMFA andCoMSIA models were constructed successfully with a good cross-validated coef-ficient (q~2) and a non-cross-validated coefficient (r~2).The q~2 and r~2 obtained fromthe leave-1-out cross validation method were 0.784 and 0.974 in the CoMFA modeland 0.736 and 0.947 in the CoMSIA model,*** coefficient isocontourmaps obtained from these models were compatible with the geometrical and physi-cochemical properties of ***:The contour map demonstrated thatthe binding affinity could be enhanced when the small protonated nitrogen moi-ety was replaced by a more hydrophobic and bulky group with a highly partialpositive *** present study provides a better understanding of the inter-action between the inhibitors and AChE,which is helpful for the discovery of newcompounds with more potency and selective activity.

关键词： molecular docking 3D-QSAR acetylcho-linesterase Alzheimer’s disease

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Conformational re-analysis of(+)-meptazinol:an opioid with mixed anal-gesic pharmacophores

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Acta Pharmacologica Sinica 2006年第9期27卷 1247-1252页

作者： Wei LI~2 Xing-hai WANG~2 Choi-wan LAU~3 Yun TANG~(2,4)Qiong XIE~2 Zhui-bai QIU~(2,5)2 Department of Medicinal Chemistry 3 NMR Laboratory,school of pharmacy,Fudan university,shanghai 200032,china 4 school of pharmacy,east china university of science and technology,shanghai 20023.,china Department of Medicinal Chemistry School of Pharmacy Fudan University Shanghai China NMR Laboratory School of Pharmacy Fudan University Shanghai China school of pharmacy East China University of Science and Technology Shanghai China

Aim:To further investigate the analgesic pharmacophore of(+)-***:Two different opioid pharmacophores,Pharm-Ⅰ and Pharm-Ⅱ,were es-tablished from structures of nine typical opiates and meperidine by using molecu-lar modeling approaches according to their different structure activity relation-ship *** were further validated by a set of conformationally con-strained *** conformers of(+)-meptazinol(Conformer-Ⅰ and Con-former-Ⅱ)detected in solution were then fitted into the pharmacophores,respectively,by Fit Atoms facilities available in SYBYL,a computational modelingtool kit for molecular design and ***:Conformer-Ⅰ fit Pharm-Ⅰ fromtypical opiates ***,Conformer-Ⅱ fit none of these ***,it was found to be similar to another potent analgesic,benzofuro[2,3-c]pyridin-6-ol,whose pharmacophore was suggested to hold the transitional statebetween the two established *** typical analgesics derivedfrom 4-aryl piperidine(eg,meperidine)with one conformer absolutely overwhelming,the(+)-meptazinol exists in two conformers with similar amounts in ***,both conformers can not transform to each other freely in ordinaryconditions based on our NMR ***:(+)-meptazinol was suggestedto be an opioid with mixed analgesic pharmacophores,which may account for thecomplicated pharmacological properties of meptazinol.

关键词： (+)meptazinol opioid analgesics arylpiperidines Conformational Analysis,pharmacophore.

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Electrochemical Characteristic of Decarburization Reaction

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International Journal of Minerals,Metallurgy and Materials 1999年第1期13卷 27-30页

作者： Xionggang Lu Fushen Li Lifen Li Kouchih Chou (Applied science school, university of science and technology Beijing, Beijing 100083, china)(Material science and Engineering school, shanghai university, shanghai 200072, china) Applied science school University of Science and Technology Beijing Beijing 100083 China Material science and Engineering school Shanghai University Shanghai 200072 China

The electrochemical mechanism of the reaction between Fe-C melts and CaO-SiO2-Al2O3-FeOx slag systems has been carried out. The experimental results suggest that the final content of carbon in melt increases as the partial oxygen pressure of gas decreases no matter whether there is electronic conductor or not. However, the final content of carbon in the system with electronic conductor is much lower than that without electronic conductor. It can be deduced that the transfer ability of oxygen in slag is dominated by electrons. When an electronic conductor exists, an easy pathway for the electrons is provided and the oxygen transfer rate is accelerated.

关键词： melt-slag reaction decarburization electrochemistry electronic conductor

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Protein Secondary Structure Prediction Using Dynamic Programming

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Acta Biochimica et Biophysica Sinica 2005年第3期37卷 167-172页

作者： Jing ZHAO Pei-Ming SONG Qing FANG Jian-Hua LUO school of Life science & technology,shanghai Jiaotong university,shanghai 200240,china shanghai Center for Bioinformation and technology,shanghai 20023.,china Logistical Engineering university,Chongqing 400016,china school of Life science & technology Shanghai Jiaotong UniversityShanghai 200240 China shanghai Center for Bioinformation and technologyshanghai 20023. China Logistical Engineering universityChongqing 400016 China

In the present paper,we describe how a directed graph was constructed and then searched forthe optimum path using a dynamic programming approach,based on the secondary structure propensity ofthe protein short sequence derived from a training data *** protein secondary structure was thus pre-dicted in this *** average three-state accuracy of the algorithm used was 76.70%.

关键词： directed graph dynamic programming approach protein secondary structure

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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 20023., 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

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A NOTE ON THE DIPERNA-LIONS FLOWS

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Acta Mathematica Scientia 2011年第5期31卷 1719-1724页

作者：刘昕黄文亮 school of Computer science and technology Huazhong University of Science and Technology Department of Mathematics East China University of Science and Technology

In this note, we give a short proof for the DiPerna-Lions flows associated to ODEs following the method of Crippa and De Lellis [3]. More precisely, assume that [divb] ∈ Ll∞oc（Rd）, ｜b｜/（1 ＋｜x｜ log ｜x｜） ∈ L∞（Rd） and ｜ b｜ φ（｜ b｜） ∈ Ll1oc（Rd）, where φ（r） = log log（r ＋ c）, c 0. Then, there exists a unique regular Lagrangian flow associated with the ODE X˙（t, x） = b（X（t, x））, X（0, x） = x.

关键词： DiPerna-Lions flow Hardy-Littlewood maximal function

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Large-eddy simulations and vortex structures of turbulent jets in crossflow

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science china(Physics,Mechanics & Astronomy) 2007年第1期50卷 118-132页

作者： GUAN Hui1,2 & WU ChuiJie2 1 school of Mechanical and Power Engineering,east china university of science and technology,shanghai 20023.,china 2 Research Center for Fluid Dynamics,PLA university of science and technology,Nanjing 211101,china school of Mechanical and Power Engineering East China University of Science and Technology Shanghai China Research Center for Fluid Dynamics PLA University of Science and Technology Nanjing China

Using the method of large-eddy simulation, the 3-dimensional turbulent jets in crossflow with stream-wise and transverse arrangements of nozzle are simulated, emphasizing on the dynamical process of generation and evolution of vortex structures in these flows. The results show that the basic vortex structures in literatures, such as the counter-rotating vortex pair, leading-edge vortices, lee-side vortices, hanging vortices, kidney vortices and anti-kidney vortices, are not independent physical substances, but local structures of the basic vortex structure of turbulent jets in crossflow-the 3-D stretching vortex rings originating from the orifice of the nozzle, which is discovered in this study. Therefore, the most important large-scale structures of turbulent jets in crossflow are unified to the 3-D vortex rings which stretch and twist in stream-wise and swing in transverse directions. We also found that the shedding frequencies of vortex rings are much lower than the one corresponding to the appearance of leading-edge and lee-side vortices in the turbulent jets.

关键词： turbulent jet in crossflow coherent structure large-eddy simulation

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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 20023.,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

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Nonsmooth Equations of K-T Systems for a Constrained Minimax Problem

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Journal of Systems Engineering and Electronics 2003年第2期14卷 31-35页

作者： Gao Yan school of Management, university of shanghai for science and technology, shanghai 200093, P. R. china school of Management University of Shanghai for Science and Technology Shanghai 200093 P. R. China

Using K-T optimality condition of nonsmooth optimization, we establish two equivalent systems of the nonsmooth equations for the constrained minimax problem directly. Then generalized Newton methods are applied to solve these systems of the nonsmooth equations. Thus a new approach to solving the constrained minimax problem is developed.

关键词： Optimization Minimax problems Nonsmooth equations Generalized Newton methods.

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Fusion Protein of Interleukin 4 and Diphtherial Toxin with High Cytotoxicity to Cancer Cells

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Acta Biochimica et Biophysica Sinica 2004年第6期36卷 437-442页

作者： Yu-Jian ZHANG, Xiao-BoHU, Su-Xia LI1, Li-Ping TIAN, Sheng-Li YANG, and Yi GONG* Research Center of Biotechnology, shanghai Institutes for Biological sciences,Chinese Academy of sciences, Graduate school of the Chinese Academy of sciences, shanghai 20023., china State Key Laboratory of Bioreactor Engineering, east china university of science and technology, shanghai 20023., china Research Center of Biotechnology Shanghai Institutes for Biological SciencesChinese Academy of Sciences Graduate School of the Chinese Academy of SciencesShanghai 200233 China State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai 200237 China

Receptor of human interleukin 4 (hIL4R) has been found to be present on many types of cancer, so it may be a good target for cancer therapy. Here, fusion toxin gene DT4H has been constructed by fusing DNA sequence encoding the first 389 amino acids of diphtherial toxin (DT), which can not bind its own receptor, to human interleukin 4 (hIL4) gene. In order to improve the affinity of fusion toxin for hIL4R, a circularly permuted form of hIL4 (cpIL4) was used. The fusion gene was expressed in Escherichia coli where the fusion toxin DT4H was highly expressed. Purified DT4H was very cytotoxic to cancer cell line U251 cells, and moderate cytotoxic to HepG2 and MCF-7 cells. SGC-7901 cells were insensitive to it. The cytotoxic action of DT4H was specific because it was blocked by excess hIL4. These results suggest that DT4H may be a useful agent in the treatment of certain malignancies.

关键词： fusion toxin diphtherial toxin cancer therapy interleukin 4 IL-4 receptor

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