National Center for Drug Screening

Shanghai, China

National Center for Drug Screening

Shanghai, China
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Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "This GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." The most exciting finding of this study is that the linker region connecting the ECD and TMD of the receptor works together with an extracellular loop of the TMD to regulate peptide binding through conformational changes, serving like a modulator in receptor activation. The researchers performed a series of functional studies to support the GCGR structure and confirm the interactions between different domains in modulating its functionality. "This study was carried out in a team effort with experts from different fields and different countries. International collaboration is of paramount importance in solving major problems in science nowadays," said Dr. Hualiang Jiang, Director of SIMM. "The full-length GCGR structure not only expands our knowledge about GPCR signaling mechanisms, but also offers new opportunities in drug discovery targeting class B GPCRs," said Dr. Ming-Wei Wang, Director of the National Center for Drug Screening. The study was funded by the National Basic Research Programs, the National Health and Family Planning Commission, the National Natural Science Foundation, Chinese Academy of Sciences and GPCR Consortium.


- Structure of the full-length human glucagon receptor ignites new excitement in GPCR research SHANGHAI, May 18, 2017 /PRNewswire/ -- A team of scientists from Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences has determined the high-resolution atomic structure of a full-length class B G protein-coupled receptor (GPCR) that plays a key role in glucose homeostasis. This structure reveals, for the first time, the structural framework of different domains of a class B GPCR at high resolution and unexpectedly discloses many exciting molecular features, greatly deepening our understanding of signaling mechanisms of class B GPCRs. The new Nature study reports the crystal structure of the full-length human glucagon receptor (GCGR) that plays a key role in glucose homeostasis and serves as an important drug target for type 2 diabetes. The image shows the overall architecture of GCGR (grey cartoon, on the right), which consists of an extracellular domain and a transmembrane domain, in complex with an antibody mAb1 and a negative allosteric modulator NNC0640 (yellow sticks). The recently published cryo-electron microscopy structure of calcitonin receptor (cyan cartoon, on the left) bound to G protein, together with the full-length GCGR structure, highlighting the recent breakthroughs in class B GPCR research. (Image courtesy of Yekaterina Kadyshevskaya of the Bridge Institute at the University of Southern California.) In an article published online in Nature on May 17, 2017 (18:00PM, London time) titled "Structure of the full-length glucagon class B G protein-coupled receptor", scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, Arizona State University and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a negative allosteric modulator (NNC0640) and the antigen-binding fragment of an inhibitory antibody (mAb1). This study is published together in Nature with a companion paper led by colleagues at the iHuman Institute, ShanghaiTech University describing the glucagon-like peptide-1 receptor (GLP-1R). Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." Class B GPCR receptors consist of an extracellular domain (ECD) and a transmembrane domain (TMD), both of which are required to interact with their cognate peptide ligands and to regulate downstream signal transduction. Due to difficulties in high-quality protein preparation, structures of full-length class B GPCRs remained elusive, thus limiting a comprehensive understanding of molecular mechanisms of receptor action. This study gives some valuable insights into the structure of GCGR. The most exciting finding is that the linker region connecting the ECD and TMD of the receptor, termed the "stalk", works together with an extracellular loop of the TMD to regulate peptide binding through conformational changes, serving like a modulator in receptor activation. "Although the stalk region only contains 12 amino acids, it acts as a 'switch' to turn on or turn off the receptor," said Dr. Wu. "It is amazing to observe how a GPCR regulates its function in such a precise and efficient way." Based on the full-length GCGR structure, the researchers performed a series of functional studies using hydrogen-deuterium exchange, disulfide cross-linking, competitive ligand binding and cell signaling assays as well as molecular dynamics simulations. The results are in support of the GCGR structure and confirm the interactions between different domains in modulating its functionality via conformational alterations. "This study was carried out in a team effort with experts from different fields and different countries. International collaboration is of paramount importance in solving major problems in science nowadays," said Dr. Hualiang Jiang, Director of SIMM. "The full-length GCGR structure not only expands our knowledge about GPCR signaling mechanisms, but also offers new opportunities in drug discovery targeting class B GPCRs," said Dr. Ming-Wei Wang, Director of the National Center for Drug Screening. "With the information gained from this structure, we are in a better position to devise new therapeutic strategies involving both GCGR and glucagon-like peptide-1 receptor for obesity and type 2 diabetes." In addition to Drs. Wu, Wang and Jiang, other study investigators included Dr. Qiang Zhao, Dr. Dehua Yang and two graduate students (Haonan Zhang and Anna Qiao) from SIMM, Dr. Linlin Yang of Zhengzhou University and Dr. Raymond Stevens from the iHuman Institute, ShanghaiTech University. The study was funded by the National Basic Research Programs, the National Health and Family Planning Commission, the National Natural Science Foundation, Chinese Academy of Sciences, Shanghai Science and Technology Development Fund, GPCR Consortium and National Institutes of Health (U.S.A.). To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/a-first-full-length-class-b-gpcr-crystal-structure-reveals-novel-receptor-activation-mechanisms-300459023.html


In an article published online in Nature on May 17, 2017 (18:00PM, London time) titled "Structure of the full-length glucagon class B G protein-coupled receptor", scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, Arizona State University and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a negative allosteric modulator (NNC0640) and the antigen-binding fragment of an inhibitory antibody (mAb1). This study is published together in Nature with a companion paper led by colleagues at the iHuman Institute, ShanghaiTech University describing the glucagon-like peptide-1 receptor (GLP-1R). Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." Class B GPCR receptors consist of an extracellular domain (ECD) and a transmembrane domain (TMD), both of which are required to interact with their cognate peptide ligands and to regulate downstream signal transduction. Due to difficulties in high-quality protein preparation, structures of full-length class B GPCRs remained elusive, thus limiting a comprehensive understanding of molecular mechanisms of receptor action. This study gives some valuable insights into the structure of GCGR. The most exciting finding is that the linker region connecting the ECD and TMD of the receptor, termed the "stalk", works together with an extracellular loop of the TMD to regulate peptide binding through conformational changes, serving like a modulator in receptor activation. "Although the stalk region only contains 12 amino acids, it acts as a 'switch' to turn on or turn off the receptor," said Dr. Wu. "It is amazing to observe how a GPCR regulates its function in such a precise and efficient way." Based on the full-length GCGR structure, the researchers performed a series of functional studies using hydrogen-deuterium exchange, disulfide cross-linking, competitive ligand binding and cell signaling assays as well as molecular dynamics simulations. The results are in support of the GCGR structure and confirm the interactions between different domains in modulating its functionality via conformational alterations. "This study was carried out in a team effort with experts from different fields and different countries. International collaboration is of paramount importance in solving major problems in science nowadays," said Dr. Hualiang Jiang, Director of SIMM. "The full-length GCGR structure not only expands our knowledge about GPCR signaling mechanisms, but also offers new opportunities in drug discovery targeting class B GPCRs," said Dr. Ming-Wei Wang, Director of the National Center for Drug Screening. "With the information gained from this structure, we are in a better position to devise new therapeutic strategies involving both GCGR and glucagon-like peptide-1 receptor for obesity and type 2 diabetes." In addition to Drs. Wu, Wang and Jiang, other study investigators included Dr. Qiang Zhao, Dr. Dehua Yang and two graduate students (Haonan Zhang and Anna Qiao) from SIMM, Dr. Linlin Yang of Zhengzhou University and Dr. Raymond Stevens from the iHuman Institute, ShanghaiTech University. The study was funded by the National Basic Research Programs, the National Health and Family Planning Commission, the National Natural Science Foundation, Chinese Academy of Sciences, Shanghai Science and Technology Development Fund, GPCR Consortium and National Institutes of Health (U.S.A.). To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/a-first-full-length-class-b-gpcr-crystal-structure-reveals-novel-receptor-activation-mechanisms-300459023.html


Zhang X.,East China Normal University | Kong Y.,East China Normal University | Zhang J.,CAS Shanghai Institute of Materia Medica | Su M.,National Center for Drug Screening | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2015

A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 Combining double low line 2-105 nM). © 2015 Elsevier Masson SAS.


Hu H.-N.,State Key Laboratory of Drug Research | Hu H.-N.,National Center for Drug Screening | Zhou P.-Z.,CAS Shanghai Institute of Materia Medica | Chen F.,State Key Laboratory of Drug Research | And 5 more authors.
Acta Pharmacologica Sinica | Year: 2013

Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC 50 value=0.10±0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors. © 2013 CPS and SIMM.


Gao X.,Fudan University | Zhao X.-L.,Fudan University | Zhu Y.-H.,CAS Shanghai Institute of Materia Medica | Li X.-M.,Fudan University | And 4 more authors.
Life Sciences | Year: 2011

Aims: Tetramethylpyrazine (TMP), one of the active ingredients isolated from a Chinese herbal prescription, possesses protective effects against oxidative stress caused by high glucose in endothelial cells. In this study, the role of TMP in preventing muscle cells from palmitate-induced oxidative damage was investigated and the possible mechanisms of action elucidated. Main methods: Mitochondrial reactive oxygen species (ROS) were measured in C2C12 myotubes, a palmitate-induced oxidative stress cell model, with or without TMP. Both mitochondrial membrane potential (MMP) and oxygen consumption were assessed in conjunction with quantification of mitochondrial DNA and mitochondrial biogenesis-related factors, such as peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (Tfam), by real-time polymerase chain reaction. Expression of mitochondrial respiratory chain complex III as an index of mitochondrial function was evaluated by immunoblotting, and glucose transport into the C2C12 myotube examined by analyzing 2-deoxy-[ 3H]glucose uptake. Key findings: TMP significantly alleviated palmitate-induced mitochondrial ROS production, mitigated mitochondrial dysfunction and increased D-loop mRNA expression as compared with the control. This was accompanied by a marked reversal of palmitate-induced down-regulation in the expression of mitochondrial biogenesis-related factors (PGC1α, NRF1 and Tfam) and decreased glucose uptake in C2C12 myotubes. As a result, cell respiration, as reflected by the elevated expression of mitochondrial respiratory chain complex III and oxygen consumption, was enhanced. Significance: TMP is capable of protecting C2C12 myotubes against palmitate-induced oxidative damage and mitochondrial dysfunction, and improving glucose uptake in muscle cells partially through the up-regulation of mitochondrial biogenesis. © 2011 Elsevier Inc.


Wantha S.,Ludwig Maximilians University of Munich | Wantha S.,RWTH Aachen | Alard J.-E.,Ludwig Maximilians University of Munich | Megens R.T.A.,Ludwig Maximilians University of Munich | And 13 more authors.
Circulation Research | Year: 2013

RATIONALE:: The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood. OBJECTIVE:: To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflammation. METHODS AND RESULTS:: Here, we show that neutrophil-derived cathelicidins (human: LL37, mouse: CRAMP) induce adhesion of classical monocytes but not of nonclassical monocytes in the mouse cremaster muscle and in in vitro flow chamber assays. CRAMP is released from emigrated neutrophils and then transported across the endothelium, where it is presented to rolling leukocytes. Endothelial-bound cathelicidin activates formyl-peptide receptor 2 on classical monocytes, resulting in monocytic β1- and β2-integrin conformational change toward an extended, active conformation that allows for adhesion to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. CONCLUSIONS:: These data elucidate a novel mechanism of neutrophil-mediated monocyte recruitment, which could be targeted in conditions where recruitment of classical monocytes plays an unfavorable role. © 2013 American Heart Association, Inc.


Ye Q.,Zhejiang University | Ye Q.,Zhejiang University of Technology | Shen Y.,Anyang Institute of Technology | Zhou Y.,National Center for Drug Screening | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of 7-azaindazolyl-indolyl-maleimides were designed, synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited potent activity against GSK-3β. Among them, compounds 17a, 17b, 17g, 17i, 29a and 30 significantly reduced Aβ-induced Tau hyperphosphorylation, showin;g the inhibition of GSK-3β at the cell level. Preliminary structure-activity relationships were discussed based on the experimental data obtained. © 2013 Elsevier Masson SAS. All rights reserved.


Huang W.,Zhejiang University | Lv D.,Zhejiang University | Yu H.,National Center for Drug Screening | Sheng R.,Zhejiang University | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a-d, 9a-g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85 ± 2.46 μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228. © 2010 Elsevier Ltd.


Huang W.,Zhejiang University | Huang W.,Chinese Institute of Materia Medica | Tang L.,Zhejiang University | Shi Y.,Zhejiang University | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H 3R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H 3R/AChE/BACE 1 (H 3R antagonism, IC 50 = 280.0 ± 98.0 nM; H 3R inverse agonism, IC 50 = 189.3 ± 95.7 nM; AChE, IC 50 = 483 ± 5 nM; BACE 1, 46.64 ± 2.55% inhibitory rate at 20 μM) and high selectivity over H 1R/H 2R/H 4R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes. © 2011 Elsevier Ltd. All rights reserved.

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