eLife
·
2024
·
IF 6.4
Tian Yuan,Yifan Wang,Yuchen Jin,Hui Yang,Shuai Xu,Heng Zhang,Qian Chen,Na Li,Xinyue Ma,Huifang Song,Chao Peng,Ze Geng,Jie Dong,Guifang Duan,Qi Sun,Yang Yang,Fan Yang,Zhuo Huang
Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Nature Chemical Biology
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2015
·Vol. 11
·期 12
·904-905
·
IF 12.996
Macarron Ricardo
Wassermann, A.M. et al. Nat. Chem. Biol. doi:10.1038/nchembio.1936 (19 October 2015).Article CAS Google Scholar Polishchuk, P.G. et al. J. Comput. Aided Mol. Des. 27, 675–679 (2013).Article CAS Google Scholar Huggins, D.J. et al. ACS Chem. Biol. 6, 208–217 (2011).Article CAS Google Scholar Baell, J.B. & Holloway, G.A. J. Med. Chem. 53, 2719–2740 (2010).Article CAS Google Scholar Leeson, P.D. & Springthorpe, B. Nat. Rev. Drug Discov. 6, 881–890 (2007).Article CAS Google Scholar Download references
研究领域:
药物化学
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化学生物学
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DOI
PubMed
高影响因子
eFood
·
2022
·Vol. 3
·期 4
·e26
·
IF 0
Yuan Liang,Tiehua Zhang
Epidermal growth factor receptor (EGFR) is among the first discovered transmembrane receptor tyrosine kinases. Ligand binding to the extracellular domain of EGFR results in the formation of homo-dimeric or hetero-dimeric complexes, activation, and auto-phosphorylation in the intracellular tyrosine kinase domain, then regulates the cell's proliferation, differentiation, migration, and invasion. It has been reported that EGFR is overexpressed, amplified, or mutated in several epithelial tumors. EGFR tyrosine kinase inhibitors (EGFR-TKIs) specifically bind to the tyrosine kinase domain of EGFR. Homogeneous time-resolved fluorescence (HTRF) assay is successfully used in kinase assays and is a crucial tool in the drug discovery of various kinases. Moreover, the HTRF assay has been determined to exhibit many advantages, such as being easy to miniaturize, simple to read, and excellent to repeat. In these guidelines, the theory, materials, and reagent preparation of HTRF kinase assay are described and emphasized. Furthermore, the protocol and optimization of the assay are determined to establish an HTRF screening platform, then an optimized HTRF kinase assay is performed to test the compounds for screening potential EGFR-TKIs. In addition, these guidelines can contribute to verifying the high-throughput screening results of HTRF and help to reveal the underlying mechanism of the EGFR kinase and tested compounds.
研究领域:
药理学
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分子生物学
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癌症研究
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DOI
APPLIED ENERGY
·
2019
·
IF 8.426
Haitao Zhao,Collins I. Ezeh,Weijia Ren,Wentao Li,Cheng Heng Pang,Chenghang Zheng,Xiang Gao,Tao Wu
The detrimental impact of urban airborne Hg 0 from fossil fuel utilization has necessitated the discovery and development of Hg 0 sensing materials for effective Hg 0 detection and mitigation of the pollutant. Earlier studies have hypothetically and experimentally supported 2-dimensional transition-metal dichalcogenides (2D TMDCs), particularly MoS 2 to have excellent performance for Hg 0 removal. However, the potential of other TMDCs is yet to be investigated for Hg 0 sensor application. In this study, a total of 28 transition metals within periods 4–6 of the periodic table, excluding the lanthanides series, were examined. To ensure proper data management flow, a high-throughput data mining approach with integrated machine learning and cheminformatics simulation approaches is developed. The systemic approach integrates the Pymatgen, Factsage, Aflow and density functional theory simulation tools for accelerated discovery of suitable TMDCs from raw data via the chemical vapour reaction route. Predicted results showed that TiS 2 , NiS 2 , ZrS 2 , MoS 2 , PdS 2 and WS 2 exhibited TMDCs characteristics. Furthermore, first-principles calculation shows Hg-uptake capacity is in the order NiS 2 > PdS 2 > TiS 2 > ZrS 2 > WS 2 > MoS 2 , while Hg sensing response is in the order PdS 2 > MoS 2 > WS 2 > ZrS 2 > NiS 2 > TiS 2 . Accordingly, PdS 2 depicted to be the most suitable TMDCs for airborne Hg 0 sensor application. The proposed systemic approach is an initial platform for materials discovery using integrated machine learning approaches and is well-suited for the screening and the discovery of new materials based on component-oriented structures.
研究领域:
材料科学
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环境科学
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化学信息学
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DOI
高影响因子
TALANTA
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2019
·
IF 4.916
Guorong Cheng,Zifeng Pi,Zhong Zheng,Shu Liu,Zhiqiang Liu,Fengrui Song
Lactate dehydrogenase (LDH), catalyzing the conversion of pyruvate to lactate during glycolysis, is overexpressed in cancer cells. LDH inhibitors are a promising approach for the treatment of cancer. But up till now, there is limited method for rapid screening of LDH inhibitors. Herein, the use of LDH functionalized magnetic nanoparticles as a drug discovery tool for the selective enrichment of LDH potential inhibitors from natural products was firstly reported in this study. Firstly, LDH was immobilized onto the surface of amino-modified magnetic nanoparticles via covalent binding. In order to obtain the maximum enzyme activity , the immobilization conditions including pH, time and LDH concentration were optimized. The amount of LDH immobilized on MNPs was about 49 μg enzyme/mg carrier under the optimized conditions. Subsequently, the ligand fishing assay was performed to validate the specificity and selectivity of immobilized LDH using a model mixture, which consisted of galloflavin, chlorogenic acid and verbascoside. Finally, the immobilized LDH approach combined with ultra-high performance liquid chromatography-tandem mass spectrometry technique (UHPLC-MS/MS) was applied to screen potential LDH inhibitors from two anthraquinone-rich natural products ( Rhubarb and Polygonum cuspidatum ). Nine and six compounds were identified from Rhubarb and Polygonum cuspidatum extracts respectively, of which three compounds were common to both. Our results have proven that LDH functionalized magnetic nanoparticles have a significant prospect for drug discovery from complex matrices.
研究领域:
生物化学
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药学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2019
·Vol. 11
·期 29
·3641-3647
·
IF 2.378
Chanjuan Liu,Chao Li,Guoyun Li,Guangli Yu
The specific interaction of carbohydrates and hemagglutinin (HA) on influenza A virus (IAV) is of great interest for carbohydrate-based anti-IAV drug discovery. Herein, a carbohydrate microarray-based method was developed for the determination of the specific interaction between carbohydrates and HA. Four marine acidic saccharides from algin (L-guluronic acid, GulA; L-diguluronic acid, GulA2; L-triguluronic acid, GulA3; and L-tetraguluronic acid, GulA4) were immobilized on poly(2-hydroxyethyl methacrylate)-cyanuric chloride-modified substrates, recently reported by us, to form a microarray. GulA, GulA2, GulA3, and GulA4 all showed specific binding with HA from influenza A H1N1 subtype and exhibited increased binding affinity. Molecular docking was adopted to simulate the complexes formed by investigated saccharides and HA to gain better insight into their binding behaviors. The reliability of the carbohydrate microarray-based assay was also verified by cytopathic effect inhibition assay and surface plasmon resonance analysis. By adopting this microarray-based method, the consumption of saccharides could be reduced to the pmol level and the limit of detection of HA could be reduced to 8.4 nM without any further signal amplification. This carbohydrate microarray-based assay is thus an ideal tool for studying specific interactions of carbohydrates and HA or other proteins, and will provide a promising platform for carbohydrate-based drug discovery and development.
研究领域:
病毒学
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生物化学
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分子生物学
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药学
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产品关联
DOI
高影响因子
JOURNAL OF CELLULAR BIOCHEMISTRY
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2017
·Vol. 119
·期 4
·3510-3518
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IF 3.085
Denan Zhang,Lei Liu,Lin Pang,Qing Jin,Kehui Ke,Ming Hu,Jingbo Yang,Weifang Ma,Hongbo Xie,Xiujie Chen
Glycogen synthase kinase-3 beta (GSK-3 β ) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3 β activity have been implicated in diabetes, heart disease, Parkinson disease, and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3 β were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Twenty selected compounds were tested, which led to the discovery of two hits. Compound 14 (IC 50 = 8.48 µM) and compound 19 (IC 50 = 2.19 µM) were identified with high affinity. Molecular dynamics (MD) simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the binding modes and energetics of GSK-3 β inhibitors. The detailed analysis of molecular dynamics results shows that Ile62, Val70, Tyr134, and Leu188 in GSK-3 β are key residues responsible to the binding of compound 14 and compound 19 . Importantly, our results also validated this combined virtual screening and biophysical technique approach to discovery kinase inhibitors, which may be applied for future inhibitor discovery work for GSK-3 β .
研究领域:
生物信息学
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药理学
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结构生物学
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2024
·
IF 18.5
Jieru Chen,Xiaoxuan Lin,Fang Sun,Huilin Wen,Zhenxiang Huang,Wenying Li,Le Jiang,Ziyi Yu,Chi Hu
Progress in the discovery of potent antibodies for therapeutic and research purposes has been accelerated by mining the antibody repertoire of plasma cells and plasmablasts. Magnetic activated cell sorting (MACS) is a well recognized method for cell sorting, however, secreted IgGs rapidly diffuse away from cells, therefore requiring specialized technique to compartmentalize individual cells and capture their secretions for MACS isolation. To this end, a scalable method to prepare hydrogel-based microcontainers for single cell culture and subsequent sorting based on their secreted IgG products at high-throughput level are described. In situ crosslinkable microgels featuring tunable viscosity are fabricated to act as soft compartments that accommodate delicate primary cells and capture secreted proteins, while providing solid supports after solgel transition to enable immune recognition with chemically functionalized magnetic nanorods in aqueous medium for MACS separation. Splenocytes are sorted based on antigen-specific IgG production from mice immunized with an antibiotic target ceftriaxone sodium, enriching a population of 220 000 000 to 800 000 prevalence following sorting. This enrichment ratio is substantially higher than conventional fluorescence activated cell sorting (FACS) methods, likely due to the multivalency of the antigen-conjugated magnetic nanorods.
研究领域:
生物技术
·
免疫学
·
分子生物学
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DOI
高影响因子
Journal of Pharmaceutical Analysis
·
2020
·
IF 2.673
Dandan Xia,Baoling Liu,Xiaowei Xu,Ya Ding,Qiuling Zheng
Drug target discovery is the basis of drug screening. It elucidates the cause of disease and the mechanism of drug action, which is the essential of drug innovation. Target discovery performed in biological systems is complicated as proteins are in low abundance and endogenous compounds may interfere with drug binding. Therefore, methods to track drug-target interactions in biological matrices are urgently required. In this work, a Fe 3 O 4 nanoparticle-based approach was developed for drug-target screening in biofluids. A known ligand-protein complex was selected as a principle-to-proof example to validate the feasibility. After incubation in cell lysates, ligand-modified Fe 3 O 4 nanoparticles bound to the target protein and formed complexes that were separated from the lysates by a magnet for further analysis. The large surface-to-volume ratio of the nanoparticles provides more active sites for the modification of chemical drugs. It enhances the opportunity for ligand-protein interactions, which is beneficial for capturing target proteins, especially for those with low abundance. Additionally, a one-step magnetic separation simplifies the pre-processing of ligand-protein complexes, so it effectively reduces the endogenous interference. Therefore, the present nanoparticle-based approach has the potential to be used for drug target screening in biological systems.
研究领域:
分析化学
·
药学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Materiomics
·
2023
·
IF 9.4
Hong Meng,Peng Wei,Zhongyu Tang,Hulei Yu,Yanhui Chu
Herein we establish formation ability descriptors of high-entropy rare-earth monosilicates (HEREMs) via the data-driven discovery based on the high-throughput solid-state reaction and machine learning (ML) methods. Specifically, adequate high-quality data are generated with 132 samples synthesized by the self-developed high-throughput solid-state reaction apparatuses, and 30 potential descriptors are considered in ML simultaneously. Two classifications are proposed to study the phase formation of HEREMs via the ML approach combined with the genetic algorithm: (Ⅰ) to distinguish pure HEREMs (X) from other phases and (Ⅱ) to categorize the detail phases of HEREMs (X2, X1, or X2+X1). Four formation ability descriptors ( r Me ¯ , E F ¯ , δ E g , and δ Z ∗ ) with a high validation accuracy (96.2%) are proposed as the optimal combination for Classification Ⅰ, where a smaller r Me ¯ is determined to have the most significant influence on the formation of HEREMs. For Classification Ⅱ, a 100% validation accuracy is achieved by using only two formation ability descriptors ( r ion ¯ and δ Z ∗ ), where the r ion ¯ is analyzed to be the dominant feature and a lower r ion ¯ is beneficial to the formation of X2-HEREMs. Based on our established formation ability descriptors, 6,045 unreported multicomponent silicates are explored, and 3,478 new HEREMs with 2,700 X2-and 423 X1-HEREMs are predicted.
研究领域:
材料科学
·
数据科学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ORGANIC CHEMISTRY
·
2024
·
IF 3.3
Shuxiong Han,Min Liang,Wenjie Ju,Junrui Wang,Xu Xu,Zhibin Huang,Yingsheng Zhao
This work reports the mild and efficient Ru-catalyzed trifluoroisopropylation of arenes using 2-bromo-1,1,1-trifluoropropane. Various bioactive molecules, such as purine and nucleoside derivatives, were well-suited for this transformation, affording the corresponding products in moderate-to-good yields. This method provides an efficient strategy for synthesizing trifluoroisopropyl molecules for drug discovery.
研究领域:
有机化学
·
药物化学
·
催化
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DOI
高影响因子
JOURNAL OF MEMBRANE BIOLOGY
·
2017
·Vol. 250
·期 5
·483-492
·
IF 1.696
Chai Ran,Chen Yafei,Yuan Hongbo,Wang Xuzhao,Guo Shuai,Qi Jinlong,Zhang Hailin,Zhan Yong,An Hailong
Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Dysfunction of the CaCCs is implicated in many diseases. Drug discovery targeting at CaCCs has recently become possible with the determination that TMEM16A is the molecular identity of CaCCs. In this study, we demonstrated that resveratrol (RES), a Chinese traditional medicine compound, is a novel activator of TMEM16A. The yellow fluorescence protein quenching assay and measurement of intracellular calcium fluorescence intensity show that RES activates TMEM16A channels in an intracellular Ca 2+ -independent way. The data of inside-out patch clamp revealed that RES dose-dependently activates TMEM16A (EC 50 = 47.92 ± 9.35 μM). Furthermore, RES enhanced the contractions of the ileum of guinea pigs by activating the TMEM16A channel, which indicated that RES might be a promising drug for the treatment of gastrointestinal hypomotility. As RES was able to induce TMEM16A channel activation, TMEM16A can be added to the list of RES drug targets.
研究领域:
药理学
·
生理学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）