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排序方式: 共有10000条查询结果,搜索用时 31 毫秒
1.
Dr. Jie Zang Dr. Fei Ye Dr. Sara M. Ø. Solbak Dr. Lars J. Høj Prof. Mingjie Zhang Prof. Anders Bach 《ChemMedChem》2021,16(6):949-954
Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors. 相似文献
2.
Viktoria M. S. Kjær Loukas Ieremias Dr. Viktorija Daugvilaite Dr. Michael Lückmann Prof. Thomas M. Frimurer Prof. Trond Ulven Prof. Mette M. Rosenkilde Dr. Jon Våbenø 《ChemMedChem》2021,16(17):2623-2627
The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch. 相似文献
3.
Marc De Doncker Chloé De Graeve Dr. Jorick Franceus Dr. Koen Beerens Prof. Vladimír Křen Dr. Helena Pelantová Dr. Ronny Vercauteren Prof. Dr. Tom Desmet 《Chembiochem : a European journal of chemical biology》2021,22(23):3319-3325
The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d -glucosyl-d -galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d -glucosyl-d -galactose and 4-O-β-d -glucosyl-l -arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis. 相似文献
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诱导式卫星欺骗干扰可诱导航空器逐渐偏离预定航迹,难以被发现,因此及时有效地检测干扰是飞行安全的保障。在现有紧组合导航体制基础上,设计了一种基于误差估值累加开环校正的紧组合导航结构,并证明了其性能与传统闭环校正紧组合导航性能等效。在此结构中,将紧组合导航系统与自适应序贯概率比检测方法结合,提出了一种基于误差估值累加开环校正的诱导式欺骗检测方法,融合紧组合导航信息与其他不受欺骗影响的导航信息,构建欺骗检测统计量进行诱导式欺骗检测。仿真结果表明,开环校正结构可避免随时间累加的惯性导航系统误差所导致的组合导航滤波器发散问题,同时欺骗检测方法可进一步提高算法对“最坏”情形下微小诱导式欺骗的检测效果。 相似文献
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7.
Dr. Ala Jo Mingi Kim Dr. Jong In Kim Jaeyoung Ha Yoon Soo Hwang Hyunsung Nam Dr. Injae Hwang Dr. Jae Bum Kim Prof. Seung Bum Park 《ChemMedChem》2021,16(7):1104-1115
Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α–UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities. 相似文献
8.
To efficiently link the continuum mechanics for rocks with the structural statistics of rock masses,a theoretical and methodological system called the statistical mechanics of rock masses(SMRM)was developed in the past three decades.In SMRM,equivalent continuum models of stressestrain relationship,strength and failure probability for jointed rock masses were established,which were based on the geometric probability models characterising the rock mass structure.This follows the statistical physics,the continuum mechanics,the fracture mechanics and the weakest link hypothesis.A general constitutive model and complete stressestrain models under compressive and shear conditions were also developed as the derivatives of the SMRM theory.An SMRM calculation system was then developed to provide fast and precise solutions for parameter estimations of rock masses,such as full-direction rock quality designation(RQD),elastic modulus,Coulomb compressive strength,rock mass quality rating,and Poisson’s ratio and shear strength.The constitutive equations involved in SMRM were integrated into a FLAC3D based numerical module to apply for engineering rock masses.It is also capable of analysing the complete deformation of rock masses and active reinforcement of engineering rock masses.Examples of engineering applications of SMRM were presented,including a rock mass at QBT hydropower station in northwestern China,a dam slope of Zongo II hydropower station in D.R.Congo,an open-pit mine in Dexing,China,an underground powerhouse of Jinping I hydropower station in southwestern China,and a typical circular tunnel in Lanzhou-Chongqing railway,China.These applications verified the reliability of the SMRM and demonstrated its applicability to broad engineering issues associated with jointed rock masses. 相似文献
9.
Tetsuya Iida Dr. Yukihiro Itoh Yukari Takahashi Dr. Yasunobu Yamashita Dr. Takashi Kurohara Dr. Yuka Miyake Prof. Makoto Oba Prof. Takayoshi Suzuki 《ChemMedChem》2021,16(10):1609-1618
Lysine demethylase 5 C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti-prostate cancer agents, and recently we identified triazole 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays, but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein-knockdown strategy. Compound 3 b , which was designed based on compound 1 , degraded KDM5C and inhibited the growth of prostate cancer PC-3 cells more strongly than compound 1 . These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C. 相似文献
10.