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1.
Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain 总被引:1,自引:0,他引:1
Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial
mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such
a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral
agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular
basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein,
a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found
that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues,
thereby activating phosphorylation of NS1.
Figure Superposition of snapshots picked from the two molecular dynamic (MD) trajectories: a H5N1 NS1 homology model and b non-H5N1 NS1 crystal structure after 0 (green ribbon), 5 (blue ribbon) and 10 ns (pink ribbon) MD simulation 相似文献
2.
Hye Won Lee Chanho Park Je-Gun Joung Minyong Kang Yun Shin Chung Won Joon Oh Seon-Yong Yeom Woong-Yang Park Tae Jin Kim Seong Il Seo 《Current issues in molecular biology》2021,43(1):226
Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery. 相似文献
3.
Self-organizing molecular field analysis (SOMFA), a new three-dimensional quantitative structure-activity relationship (3-D-QSAR) method is used to study the correlation between the molecular properties and the alpha(1a)-AR biological activities of dihydropyridine derivatives. The statistical result, cross-validated q(2) (0.690) and non cross-validated r(2) (0.704) values, show a good predictive ability. 相似文献
4.
Xiaojian Wang Qian Yang Minyong Li Dali Yin Qidong You 《Journal of molecular modeling》2010,16(9):1529-1537
It is widely acknowledged that the H1 receptor antagonists have important therapeutic significance in the treatment of various allergic disorders, but little was
known about the binding mode between the receptor and antagonists since the crystal structure of G-protein coupling receptors
(GPCRs) were hard to obtain. In this paper, a theoretical three-dimensional model of human histamine H1 receptor (HHR1) was developed on the basis of recently reported high resolution structures of human A2A adenosine receptor, human β2-adrenoceptor and turkey β1-adrenoceptor. Furthermore, three representative H1 receptor antagonists were chosen for docking studies. Subsequently, a qualitative pharmacophore model was developed by Hiphop
algorithm based on the docking conformations of these three antagonists. In this paper, active environment, certain key residues,
and the corresponding pharmacophore features of H1 receptor were identified by such combinations of receptor-based and ligand-based approaches, which would give sufficient
guidance for the rational design of novel antihistamine agents. 相似文献
5.
Bacteria can coordinate community-wide behaviors through quorum sensing, that is, the secretion and sensing of autoinducer (AI) molecules. Bacterial quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, bacterial virulence, and drug resistance. Inhibitors of bacterial quorum sensing could therefore be useful therapeutics. Herein we report for the first time the discovery of several pyrogallol compounds as single digit micromolar inhibitors of bacterial quorum sensing in Vibrio harveyi. 相似文献
6.
Tsai KC Wang SH Hsiao NW Li M Wang B 《Bioorganic & medicinal chemistry letters》2008,18(12):3509-3512
As a commonly used structure-based approach for virtual screening, molecular design and lead optimization, molecular docking can search the preferred orientation and conformation of a ligand for its optimal binding to a receptor or enzyme active site. In doing so, selecting an appropriate method to calculate the electrostatic potentials is critical. In the current report, nine different semi-empirical and empirical methods, including AM1, AM1-BCC, Del-Re, MMFF, Gasteiger, Hückel, Gasteiger-Hückel, Pullman and formal charges were investigated for their performance on the prediction of docking poses using the DOCK5.4 program. The results demonstrated that the AM1-BCC charges had the highest success rate. 相似文献
7.
Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small molecule inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small molecule inhibitors of Tip60 as mechanistic tools for functional study and as chemical leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small molecule library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compounds with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochemical studies. Further, computer modeling and kinetic assays suggest that these molecules target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chemical hits to develop further potent inhibitors for the MYST HATs. 相似文献
8.
Shan Jin Chunyuan Zhu Yunfeng Cheng Minyong Li Binghe Wang 《Bioorganic & medicinal chemistry》2010,18(4):1449-1455
Fluorescent boronic acids are very useful for the design and synthesis of carbohydrate sensors. In an earlier communication, we first described the effort of developing water soluble fluorescent α-amidoboronic acids, which change fluorescence upon sugar binding. In this report, we describe a general method of functionalizing such boronic acids and their applications in the preparation of bis-α-amidoboronic acids with significantly enhanced binding for oligosaccharides as compared to their monoboronic acid counterparts. The advantages of good water solubility, easy modification to generate diversity, and modularity in synthesis will make α-amidoboronic acids very useful building blocks for future synthesis of boronic acid-based fluorescent sensors. 相似文献
9.
Lupei Du Minyong Li Qian Yang Yiqun Tang Qidong You Lin Xia 《Bioorganic & medicinal chemistry letters》2009,19(5):1477-1480
The combination of IKr and IKs blockade could lead to synergistic and safe class III anti-arrhythmic effect with the enhanced efficacy and reduced risk. On the rationale of structural hybridization of azimilide and HMR-1556, a novel series of IKr and IKs dual blockers were designed, synthesized and evaluated in vitro. One compound, 3r (CPUY11018), deserves further evaluation for its potent anti-arrhythmic activity and favorable cardiovascular profile. 相似文献
10.
Shan Jin Chunyuan Zhu Minyong Li Binghe Wang 《Bioorganic & medicinal chemistry letters》2009,19(6):1596-1599
The first amidoboronic acids were identified that show significant fluorescent property changes upon binding with various carbohydrates. 相似文献