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Synthesis of 5-substituted benzyl-2,4-diamino pyrimidine derivatives as c-Fms kinase inhibitors

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Chinese Chemical Letters 2010年第11期21卷 1318-1321页

作者： Li Bao Xu Wei Sun Hong Ying Liu Li Li Wang Jun Hai Xiao Xiao Hong Yang Song Li School of Pharmaceutical Sciences Jilin University Changchun 130021 China laboratory of computer-aided drug design & discovery Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

A serials of novel 5-substituted benzyl-2,4-diamino pyrimidine derivatives have been synthesized and evaluated as inhibitors of c-Fms kinase by the standard MTT *** results showed that compound 15,5-[3-methoxy-4-（pyridine-3-yl）benzyl]-2,4-diamino pyrimidine,had an IC50 of 1.45μmol/L in inhibiting the proliferation of M-CSF-dependent myeloid leukemia cells in mice （NFS-60）,which was similar with GW2580,a selective inhibitor of c-Fms kinase.

关键词： C-Fms kinase inhibitors Synthesis 2 4-Diamino pyrimidine

Quantification of flupirtine maleate polymorphs using X-ray powder diffraction

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Chinese Chemical Letters 2016年第11期27卷 1666-1672页

作者： Yu-Mei Zhao Zhi-Bing Zheng Song Li laboratory of computer-aided drug design & discovery Beijing Institute of Pharmacology and Toxicology laboratory of Structure Identification Beijing Institute of Pharmacology and Toxicology State Key laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crystal form. Unfortunately, it is usually found in a polymorphic mixture with form B. In this study, pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction （XRPD）, Fourier transform infrared spectroscopy （FT-IR） and thermal analysis. An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters. The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0- 100% （w/w）, good linear relationship, with R2= 0.999, excellent repeatability and precision and low limits of detection （LoD） of 0.15% （w/w） and quantification （LoQ） of 0.5% （w/w）. The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation, but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good, repeatable, sensitive, and accurate method. This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs （forms A and B） quantitatively and control the quality of the bulk drug.

关键词： Flupirtine maleate X-ray powder diffraction Quantitative analysis of polymorphs Preferred orientation Transmission

Syntheses and studies of hydantoin derivatives as potential anti-tuberculosis inhibitors

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Chinese Chemical Letters 2012年第2期23卷 133-136页

作者： Yan Liu Wu Zhong Song Li School of Pharmaceutical Engineering Shenyang Pharmaceutical UniversityShenyang 110016China laboratory of computer-aided drug design&discovery Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

A short and efficient synthesis of（Z）-2-substituted-5-（4-（（2-substitued-5-oxoimidazolidin-4-ylidene）methyl）benzamido）ben-zoic acid derivatives（8a-g） as potential type of FabH inhibitors is *** structures wer... 详细信息

关键词： Tuberculosis Mycobacterium tuberculosis FabH Enzyme inhibitor Synthesis NOE

design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists

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Chinese Journal of Chemistry 2013年第9期31卷 1144-1152页

作者： Wei Sun Linjie Tian Hui Qi Dan Jiang Ying Wang Song Li Junhai Xiao Xiaohong Yang School of Pharmaceutical Sciences Jilin University Changchun Jilin 130021 China laboratory of computer-aided drug design & discovery Beijing Institute of Pharmacology & Toxicology Beij'ing 100850 China Center for Human Disease Genomics Peking University Beijing 100083 China

A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 （CCR4） antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric con- figurations of the compounds were identified by 2D I H-~H COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the inter- actions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, lc is the most active one. Its apparent binding constant of CZE experiment result is （1.569±0.11）× 10s L·mol ^-1, and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of I gmol·L ^-1 in DMSO is 59%. And compound If has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than lb because of the in- troduced ester linkage. Further studies on the mechanism of these compounds are in progress.

关键词： CCR4 antagonists tri-substituted chiral pyrrolidin-2-one derivatives synthesis

Novel ligand-based docking; molecular dynamic simulations;and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

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Journal of Pharmaceutical Analysis 2018年第6期8卷 413-420页

作者： Subramaniyan Vijayakumar Palani Manogar Srinivasan Prabhu Ram Avadhar Sanjeevkumar Singh Computational Phytochemistry laboratory PG and Research Department of Botany and Microbiology AVVM Sri Pushpam College (Autonomous) Poondi computer aided drug design and Molecular Modeling laboratory Department of Bioinformatics Alagappa University

Acetylcholinesterase(AChE) plays an important role in Alzheimer's disease(AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, antiAChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic(MD) simulations; and absorption, distribution, metabolism, and excretion(ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of à 12.335 with a good binding energy value ofà73.313 kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30 ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies.

关键词： Alzheimer's disease Acetylcholinesterase Phytocompounds Molecular docking Free energy calculations Molecular dynamic simulations

Conformational flexibility of β-secretase: molecular dynamics simulation and essential dynamics analysis

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Acta Pharmacologica Sinica 2004年第6期25卷 3-11页

作者： Bing XIONG, Xiao-qin HUANG, Ling-ling SHEN, Jian-hua SHEN 2,Xiao-min LUO, Xu SHEN, Hua-liang JIANG2, Kai-xian CHENdrug discovery and design Center, State Key laboratory of drug Research, Shanghai Institute of Materia Medica,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 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 Shanghai 201203 China

AIM: Based on the structural analysis to reveal the mechanism of ligand binding to b-secretase and the specificityof each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free b-secretase andligand bound b-secretase. The trajectories were analyzed using the essential dynamics, and the significant confor-mational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDomanalyses clearly showed that the b-secretase experienced a large conformational change upon the substrate orinhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate theligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysisrevealed that residues at P2, P1, and P1 positions of the inhibitor were very important for the binding, and residuesat P2 and P3 positions may be modified to improve the binding specificity. S3 subsite of the enzyme still hadspace to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented hereis valuable and could be used to identify small molecular inhibitors of b-secretase.

关键词： molecular dynamics secretase essential dynamics computer simulation Alzheimer disease

Macleayine,a new alkaloid from Madeaya cordata

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Chinese Chemical Letters 2016年第11期27卷 1717-1720页

作者： Chun-Mei Sai Ning-Bo Qin Cui-Cui Jia Da-Hong Li Kai-Bo Wang Yue-Hu Pei Jiao Bai Zhan-Lin Li Hui-Ming Hua Key laboratory of Structure-Based drug design & discovery Ministry of Education Shenyang Pharmaceutical University Shenyang 110016 China

Macleayine （1）, a new natural occurring alkaloid with a unique spiro [furanone-piperidinedione] framework, was isolated from the aerial parts ofMacleaya cordata. Its unusual structure was established by extensive spectroscopic analyses, computer-assisted structure elucidation software （ACD/Structure Elucidator）, quantum chemistry calculations and ECD calculation. The result of virtual molecular docking predicted the compound can enhance the effects of insulin, and may be used to treat tvpe II diabetes.

关键词： Macleayine A natural occurring alkaloid Quantum chemistry calculations ECD calculation Plausible biogenetic pathway Macleaya cordata

A novel copper metabolism-related signature model for predicting the prognosis,target drugs,and immunotherapy in stomach adenocarcinoma

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Genes & Diseases 2024年第5期11卷 21-24页

作者： Kai Zhuang Siqi Tang Haixin Feng Jinying Zhang Ying Liu Yong Liu Yongjian Su Jiaqi Yu Zunnan Huang Key laboratory of computer-aided drug design of Dongguan City The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523710China Key laboratory of Big Data Mining and Precision drug design of Guangdong Medical University Key Laboratory for Research and Development of Natural Drugs of Guangdong ProvinceSchool of PharmacyGuangdong Medical UniversityDongguanGuangdong 523808China School of Public Health Guangdong Medical UniversityDongguanGuangdong 523808China Marine Biomedical Research Institute of Guangdong Zhanjiang ZhanjiangGuangdong 524203China

Stomach adenocarcinoma(STAD)is one of the most common gastric neoplasms with a high death ***,there is an urgent need to propose an efficient therapy for *** plays key roles in regulating the distribution of immune cells and affecting the tumor immune escape,and may be a novel indicator of immunotherapy in ***,the specific impact of copper metabolism-related genes(CMRGs)on the patient’s prognosis,tumor microenvironment,and immunotherapeutic response remains unelucidated.

关键词： metabolism stomach adenocarcinoma

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy

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Asian Journal of Pharmaceutical Sciences 2021年第2期16卷 203-212页

作者： Qiu Wang Mengchi Sun Chang Li Dan Li Zimeng Yang Qikun Jiang Zhonggui He Huaiwei Ding Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Key laboratory of Structure-Based drug design and discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer ***,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor ***,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer ***,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs *** on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen ***,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation *** various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical ***,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor *** a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

关键词： Photodynamic therapy Chemotherapy Self-delivery computer-aided Synergistic cancer therapy