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Drug Design of "Undruggable" Targets

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Chinese Journal of Chemistry 2019年第5期37卷 501-512页

作者： Jie Wang shiliang li Honglin li Shanghai Key Laboratory of New Drug Design School of Pharmacy East China University of Science and Technology Shanghai 200237 China

Drug innovation is not only reflected in the discovery of new chemotypes of active compounds against existing targets but also more dependent on the innovation of drug targets. Currently, a number of attractive and validated targets could not be targeted pharmacologically. Some have been described as "un druggable''.In this review, we summarized the curre nt situatio n of "undruggable" targets, and the desig n strategies for "un druggable" targets, hoping to provide references for the development of innovative drugs.

关键词： reflected chemotypes drugs

A Secure Three-Factor Authenticated Key Agreement Scheme for Multi-Server Environment

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Computers, Materials & Continua 2020年第9期64卷 1673-1689页

作者： Meichen Xia shiliang li liu liu School of Computer and Software Engineering Xihua UniversityChengdu610039China School of Software and Electrical Engineering Swinburne University of TechnologyHawthornVIC 3122Australia

Multi-server authenticated key agreement schemes have attracted great attention to both academia and industry in recent ***,traditional authenticated key agreement schemes in the single-server environment are not suitable for the multi-server environment because the user has to register on each server when he/she wishes to log in various servers for different ***,it is unreasonable to consider all servers are trusted since the server in a multi-server environment may be a semi-trusted *** order to overcome these difficulties,we designed a secure three-factor multi-server authenticated key agreement protocol based on elliptic curve cryptography,which needs the user to register only once at the registration center in order to access all semi-trusted *** proposed scheme can not only against various known attacks but also provides high computational ***,we have proved our scheme fulfills mutual authentication by using the authentication test method.

关键词： Authenticated key agreement three-factor multi-server authentication test method.

Flotation separation of calcareous minerals using didodecyldimethylammonium chloride as a collector

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International Journal of Mining Science and Technology 2012年第2期22卷 285-288页

作者： Zhang Ying Wang Yuhua li shiliang School of Minerals Processing and Bioengineering Central South UniversityChangsha 410083China Beijing General Research Institute of Mining&Metallurgy Beijing 100070China

The flotation separation of scheelite from fluorite and calcite using dodecyltrimethylammonium chloride （DTAC）, dodecyldimethylbenzylammonium chloride （DDBAC）, or didodecyldimethylammonium chloride （DDDAC） as the collector has been investigated. The results show that the selectivity of these collectors for these three calcareous minerals falls in the order： DDDAC 〉 DDBAC 〉 DTAC. A significantly different flotation response of scheelite compared to the other two calcareous minerals was observed over the pH range from 7 to 8 for DDDAC as the collector. A concentrate containing 41.40% W03 could be produced from a feed mixture containing 23.22% WO3 at the DDDAC concentration of 4.0× 10^-4 mol/L. The WO3 recovery was 92.92% under these conditions. The results of zeta potential measurements suggest that electrostatic interactions are the main forces between DDDAC and the minerals. When the concentration of DDDAC is from 2× 10^-4 to 4×10-3 mol/L large differences in adsorption density, and adsorption kinetics, of DDDAC onto scheelite, calcite, and fluorite provide desirable conditions for achieving high selectivity.

关键词： ScheeliteCalciteFluoriteFlotationQuaternary ammonium salt

Design, Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors

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Chinese Journal of Chemistry 2021年第1期39卷 115-120页

作者： Na Luo Xiaoyu Fang Mingbo Su Xinwen Zhang Dan li Honglin li shiliang li Zhenjiang Zhao Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and Technology130 Meilong RoadShanghai 200237China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences555 Zhuchongzhi RoadShanghai 201203China Shandong Biopolar Dichang Pharmaceutical Co. LtdRM2306No.786 Linzi AvenueZiboShandong 255400China

Dipeptidyl peptidase 4(DPP-4)is a clinically validated target for the treatment of type 2 diabetes mellitus(T2DM).To discover novel and potent DPP-4 inhibitors,three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2-phenyl-3,4-dihydro-2H-benzo[f]*** the designed compounds,41d-1 was the most po tent one with an IC_(50) value of 16.00 nM.

关键词： TypeⅡdiabetes Dipeptidyl peptidaseⅣ Inhibitors Molecular docking Structure-activity relationship

Discovery of a natural fluorescent probe targeting the Plasmodium falciparum cysteine protease falcipain-2

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Science China(life Sciences) 2020年第7期63卷 1016-1025页

作者： lili Zhu Lei Shan Junsheng Zhu li li shiliang li liyan Wang Jiawei Wang Shoude Zhang Hongchang Zhou Weidong Zhang Honglin li Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and TechnologyShanghai 200237China Department of Natural Product Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Medicine Huzhou UniversityHuzhou ho u Central HospitalHuzhou 313000China

The Plasmodium falciparum cysteine protease falcipain-2(FP-2) is an attractive antimalarial target. Here, we discovered that the natural compound NP1024 is a nonpeptidic inhibitor of FP-2 with an IC50 value of 0.44 μmol L–1. The most exciting finding is that both in vitro and in vivo, NP1024 directly targets FP-2 in malaria parasite-infected erythrocytes as a natural fluorescent probe, thereby paving the way for an integration of malaria diagnosis and treatment.

关键词： falcipain-2 malaria diagnosis antimalarial agent acylated flavonol monoglycoside fluorescent probe

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

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Signal Transduction and Targeted Therapy 2023年第6期8卷 2493-2549页

作者： Thian-Sze Wong Guangzhi li shiliang li Wei Gao Geng Chen Shiyi Gan Manzhan Zhan Honglin li Song Wu Yang Du Kobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and DevelopmentSchool of MedicineThe Chinese University of Hong Kong518172ShenzhenGuangdongChina School of Medicine Tsinghua University100084BeijingChina Institute of Urology The Affiliated Luohu Hospital of Shenzhen UniversityShenzhen University518000ShenzhenGuangdongChina Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and Technology200237ShanghaiChina Innovation Center for AI and Drug Discovery East China Normal University200062ShanghaiChina Department of Urology South China HospitalHealth Science CenterShenzhen University518116ShenzhenGuangdongChina

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological *** treatment targets is challenging because the diseases are resulting from heterogeneous biological,genetic,and environmental ***,the increasing understanding of G protein-coupled receptor(GPCR)opens a new possibility in drug *** our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective *** review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric ***,we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.

关键词： psychiatric disorders diseases

Triazole and Benzotriazole Derivatives as Novel Inhibitors for p90 Ribosomal S6 Protein Kinase 2： Synthesis, Molecular Docking and SAR Analysis

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Chinese Journal of Chemistry 2013年第9期31卷 1192-1198页

作者： Jun Yuan Ye Zhong shiliang li Xue Zhao Guoqin Luan Zhenjiang Zhao Jin Huang Honglin li Yufang Xu Shanghai Key Laboratory of New Drug Design State Key Laboratory of Bioreactor Engineering School of Pharmacy East China University of Science & Technology Shanghai 200237 China

A series of triazole and benzotriazole derivatives as novel p90 ribosomal S6 protein kinase 2 （RSK2） inhibitors were designed and synthesized. The in vitro activities against RSK2 were evaluated, and among 14 compounds, compounds 5, 6, 11, 12, 13 and 14 exhibited enzyme IC50 values of 8.91, 2.86, 3.19, 3.05, 4.49 and 2.09 μmol/L re- spectively. The proposed binding modes were simulated using molecular docking method, and the docking results coupled with the stmcture-activi1：y relationship （SAR） analysis indicated that all these active compounds bound to the RSK2 ATP binding site at NTKD, and the electron-donating groups on the 4-position of phenyl were the deter- minant point for the inhibitory activity.

关键词： RSK2 structure-activity relationships molecular docking

AI enhances drug discovery and development

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National Science Review 2024年第3期11卷 52-54页

作者： Fang Bai shiliang li Honglin li Shanghai Institute for Advanced Immunochemical Studies and School of life Science and Technology ShanghaiTech University lingang Laboratory Innovation Center for AI and Drug Discovery East China Normal University

The advent of the third wave of artificial intelligence(AI) heralds a new era in drug discovery. AI-powered techniques can be characteristic of identifying features that are difficult for humans to interpret from big ...

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Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

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Chinese Journal of Chemistry 2019年第12期37卷 1259-1263页

作者： Yanling Wang Huan Ge Disha Wang Huan He Lu li Yanyan Diao Zihao Shen lili Zhu shiliang li Zhenjiang Zhao Honglin li Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and Technology130 Meilong RoadShanghai 200237China

Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects,but the difficulties in drug design and synthesis of macrocycle limit its *** this study,a series of macrocyclic derivatives designed from anaplastic lymphoma kinase(ALK)inhibitor lorlatinib were synthesized as Janus kinase 2(JAK2)selective *** them,17f had the best inhibitory activity(IC50=0.177μmol·L^-1)and selectivity for JAK2 over JAK1 and JAK3,which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhihitors.

关键词： cycle macrocyclic conclusion