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排序方式: 共有8743条查询结果,搜索用时 109 毫秒
1.
Shraddha Parate Vikas Kumar Danishuddin Jong Chan Hong Keun Woo Lee 《International journal of molecular sciences》2021,22(10)
Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer. 相似文献
2.
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
3.
Verena B. K. Kunig Dr. Marco Potowski Dr. Mateja Klika Škopić Dr. Andreas Brunschweiger 《ChemMedChem》2021,16(7):1048-1062
Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein-coupled receptors (GPCRs) and kinases. The protein surface-binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small-molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points. 相似文献
4.
Dr. Louise M. Sternicki Dr. Jim Nonomiya Dr. Miaomiao Liu Dr. Melinda M. Mulvihill Dr. Ronald J. Quinn 《ChemMedChem》2021,16(14):2206-2210
PRO teolysis TA rgeting C himeras (PROTACs) promote the degradation, rather than inhibition, of a drug target as a mechanism for therapeutic treatment. Bifunctional PROTAC molecules allow simultaneous binding of both the target protein and an E3-Ubiquitin ligase, bringing the two proteins into close spatial proximity to allow ubiquitinylation and degradation of the target protein via the cell's endogenous protein degradation pathway. We utilized native mass spectrometry (MS) to study the ternary complexes promoted by the previously reported PROTAC GNE-987 between Brd4 bromodomains 1 and 2, and Von Hippel Lindeau E3-Ubiquitin Ligase. Native MS at high resolution allowed us to measure ternary complex formation as a function of PROTAC concentration to provide a measure of complex affinity and stability, whilst simultaneously measuring other intermediate protein species. Native MS provides a high-throughput, low sample consumption, direct screening method to measure ternary complexes for PROTAC development. 相似文献
5.
In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models. 相似文献
6.
Xuejie Li Yaqing Wen Jian Zhang Dongyun Ma Jie Zhang Yanxia An Xiaoyan Song Xiujuan Ren Weifeng Zhang 《International Journal of Food Science & Technology》2022,57(3):1544-1553
The effects of non-thermal plasma (NTP) on the physicochemical properties of wheat flour and the quality of fresh wet noodles ( FWN) were investigated. The results showed that NTP effectively decreased the total plate count (TPC), yeast and mould count (YMC) and Bacillus spp. in wheat flour. Wet gluten contents and the stability time reached the maximum when treated for 20 s. The viscosity of starch increased significantly after treatment due to the increased of damaged starch. The contents of secondary structure were altered to some extent, which was because that the ordered network structure of gluten protein broken. Furthermore, compared with the control, texture properties of FWN were enhanced significantly at 20 s, and the darkening rate of FWN was greatly inhibited due to the low polyphenol oxidase (PPO) activity. Consequently, the most suitable treatment was 500 W for 20 s, providing a basis for the application of NTP in flour products. 相似文献
7.
The dependence of the maximum and minimum wet thicknesses on the coating gap is derived for the slot-die coating process, under different slot-die configurations. Analytical expressions for the wet thickness and its derivative with respect to the coating gap are obtained using a simple flow model. The results indicate that, as expected, the minimum wet thickness increases linearly with the coating gap; however, the maximum wet thickness demonstrates a counterintuitive trend of decreasing as the coating gap increases, when a specific slot-die configuration is assumed. Moreover, the results are also validated by numerically solving the complete two-dimensional (2D) Navier–Stokes equation. 相似文献
8.
9.
Yu-Ting Liu Xian-Bin Li Hui Zheng Nian-Ke Chen Xue-Peng Wang Xu-Lin Zhang Hong-Bo Sun Shengbai Zhang 《Advanced functional materials》2021,31(21):2009803
Phase change memory (PCM) is an emerging non-volatile data storage technology concerned by the semiconductor industry. To improve the performances, previous efforts have mainly focused on partially replacing or doping elements in the flagship Ge-Sb-Te (GST) alloy based on experimental “trial-and-error” methods. Here, the current largest scale PCM materials searching is reported, starting with 124 515 candidate materials, using a rational high-throughput screening strategy consisting of criteria related to PCM characteristics. In the results, there are 158 candidates screened for PCM materials, of which ≈68% are not employed. By further analyses, including cohesive energy, bond angle analyses, and Born effective charge, there are 52 materials with properties similar to the GST system, including Ge2Bi2Te5, GeAs4Te7, GeAs2Te4, so on and other candidates that have not been reported, such as TlBiTe2, TlSbTe2, CdPb3Se4, etc. Compared with GST, materials with close cohesive energy include AgBiTe2, TlSbTe2, As2Te3, TlBiTe2, etc., indicating possible low power consumption. Through further melt-quenching molecular dynamic calculation and structural/electronic analyses, Ge2Bi2Te5, CdPb3Se4, MnBi2Te4, and TlBiTe2 are found suitable for optical/electrical PCM applications, which further verifies the effectiveness of this strategy. The present study will accelerate the exploration and development of advanced PCM materials for current and future big-data applications. 相似文献
10.
Bijan Nasri‐Nasrabadi Akif Kaynak Shayan Seyedin Zahra Komeily‐Nia Abbas Z Kouzani 《Polymer International》2019,68(5):922-928
Recent advances in three‐dimensional (3D) printing have enabled the fabrication of interesting structures which are not achievable using traditional fabrication approaches. The 3D printing of carbon microtube composite inks allows fabrication of conductive structures for practical applications in soft robotics and tissue engineering. However, it is challenging to achieve 3D printed structures from solution‐based composite inks, which requires an additional process to solidify the ink. Here, we introduce a wet 3D printing technique which uses a coagulation bath to fabricate carbon microtube composite structures. We show that through a facile nanogrooving approach which introduces cavitation and channels on carbon microtubes, enhanced interfacial interactions with a chitosan polymer matrix are achieved. Consequently, the mechanical properties of the 3D printed composites improve when nanogrooved carbon microtubes are used, compared to untreated microtubes. We show that by carefully controlling the coagulation bath, extrusion pressure, printing distance and printed line distance, we can 3D print composite lattices which are composed of well‐defined and separated printed lines. The conductive composite 3D structures with highly customised design presented in this work provide a suitable platform for applications ranging from soft robotics to smart tissue engineering scaffolds. © 2019 Society of Chemical Industry 相似文献