8 results on '"Zhang, Liangren"'
Search Results
2. Enrichment Assessment of Multiple Virtual Screening Strategies for Toll-Like Receptor 8 Agonists Based on a Maximal Unbiased Benchmarking Data Set.
- Author
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Pei, Fen, Jin, Hongwei, Zhou, Xin, Xia, Jie, Sun, Lidan, Liu, Zhenming, and Zhang, Liangren
- Subjects
TOLL-like receptors ,IMMUNE response ,CYTOKINES ,BINDING sites ,STRUCTURE-activity relationship in pharmacology ,MOLECULAR docking - Abstract
Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed ' mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore ( Phar1) screening, shape-based 3D similarity search ( Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
3. The Discovery of Novel Vascular Endothelial Growth Factor Receptor Tyrosine Kinases Inhibitors: Pharmacophore Modeling, Virtual Screening and Docking Studies.
- Author
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Hui Yu, Wang, Zhanli, Zhang, Liangren, Zhang, Jufeng, and Huang, Qian
- Subjects
VASCULAR endothelial growth factors ,NEOVASCULARIZATION ,RESEARCH methodology ,DRUG design ,BIOCHEMISTRY - Abstract
We have applied pharmacophore generation, database searching and docking methodologies to discover new structures for the design of vascular endothelial growth factor receptors, the tyrosine kinase insert domain-containing receptor kinase inhibitors. The chemical function based pharmacophore models were built for kinase insert domain-containing receptor kinase inhibitors from a set of 10 known inhibitors using the algorithm HipHop, which is implemented in thecatalyst software. The highest scoring HipHop model consists of four features: one hydrophobic, one hydrogen bond acceptor, one hydrogen bond donor and one ring aromatic function. Using the algorithm CatShape withincatalyst, the bound conformation of 4-amino-furo [2, 3-d] pyrimidine binding to kinase insert domain-containing receptor kinase was used to generate a shape query. A merged shape and hypothesis query that is in an appropriate alignment was then built. The combined shape and hypothesis model was used as a query to search Maybridge database for other potential lead compounds. A total of 39 compounds were retrieved as hits. The hits obtained were docked into kinase insert domain-containing receptor kinase active site. One novel potential lead was proposed based oncatalyst fit value, LigandFit docking scores, and examination of how the hit retain key interactions known to be required for kinase binding. This compound inhibited vascular endothelial growth factor stimulated kinase insert domain-containing receptor phosphorylation in human umbilical vein endothelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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- View/download PDF
4. Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.
- Author
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Liu, Yajun, Liu, Xiaoxia, Li, Lihong, Dai, Rui, Shi, Meiyun, Xue, Hongyu, Liu, Yong, Wang, Hecheng, and Zhang, Liangren
- Subjects
ADENOSINE triphosphate ,HEAT shock proteins ,BINDING sites ,STRUCTURE-activity relationships ,MOLECULAR docking ,WESTERN immunoblotting - Abstract
Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound 4a showed the highest binding affinity to Hsp90α (IC
50 = 12 nM) in fluorescence polarization (FP) competition assay and the strongest anti-proliferative activity against human breast adenocarcinoma cell line (MCF-7) and human lung epithelial cell line (A549) with IC50 values of 21.58 μM and 31.22 μM, respectively. Western blotting assays revealed that these novel Hsp90 inhibitors significantly down-regulated the expression level of Her2, a client protein of Hsp90, resulting in the cytotoxicity of these novel Hsp90 inhibitors. The molecular docking study showed that these novel Hsp90 inhibitors bound to the adenosine triphosphate (ATP) binding site at the N-terminus of Hsp90. Furthermore, structure–activity relationship studies indicated that the N-benzyl group is important for the anti-cancer activity of 1,3-dibenzyl-2-aryl imidazolidines. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
5. Discovery of novel and selective farnesoid X receptor antagonists through structure-based virtual screening, preliminary structure-activity relationship study, and biological evaluation.
- Author
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Dou, Xiaodong, Huo, Tongyu, Liu, Yameng, Pang, Zichen, Su, Lingyu, Zhao, Xinyi, Peng, Xing, Liu, Zhenming, Zhang, Liangren, and Jiao, Ning
- Subjects
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FARNESOID X receptor , *STRUCTURE-activity relationships , *LDL cholesterol , *BILE acids , *LABORATORY mice , *GLUCOSE metabolism - Abstract
Farnesoid X receptor (FXR) is a bile acids receptor and plays a crucial role in regulating bile acids, lipids, and glucose metabolism. Previous research suggests that inhibiting FXR activation can be beneficial in reducing cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, offering potential treatment options for metabolic syndrome with lipid disorders. Herein, we report p -acetylaminobenzene sulfonate derivatives as a novel scaffold of FXR antagonists by multistage screening. Among these derivatives, compound F44-A13 exhibited a half-maximal inhibitory concentration of 1.1 μM. Furthermore, compound F44-A13 demonstrated effective inhibition of FXR activation in cellular assays and exhibited high selectivity over eleven other nuclear receptors. Besides, compound F44-A13 significantly suppressed the regulation of FXR target genes Shp , Besp , and Cyp7a1 , while reducing cholesterol levels in human hepatoma HepG2 cells. Pharmacological studies conducted on C57BL/6 mice further confirmed that compound F44-A13 had beneficial effects in reducing cholesterol, triglycerides, and LDL-C levels. These findings highlight that F44-A13 is a highly selective FXR antagonist that might serve as a useful molecule for further FXR studies as well as the development of FXR antagonists for the potential treatment of metabolic diseases with lipid disorders. [Display omitted] • A series of p -acetylaminobenzene sulfonate derivatives were identified as novel and selective antagonists of FXR. • Compound F44-A13 displayed an IC 50 value of 1.1 μM, and high selectivity over eleven other nuclear receptors. • Compound F44-A13 strongly reversed the regulation of FXR target genes and reduced the cholesterol levels in HepG2 cells. • Compound F44-A13 exhibited beneficial effects on reducing cholesterol, triglycerides, and LDL-C levels in C57BL/6 mice. • The structure-activity relationship of p -acetylaminobenzene sulfonate derivatives was investigated by molecular simulation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. Design, synthesis and biological activities of 2,3-dihydroquinazolin-4(1H)-one derivatives as TRPM2 inhibitors.
- Author
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Zhang, Han, Liu, Huan, Luo, Xiao, Wang, Yuxi, Liu, Yuan, Jin, Hongwei, Liu, Zhenming, Yang, Wei, Yu, Peilin, Zhang, Liangren, and Zhang, Lihe
- Subjects
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QUINAZOLINE , *TRP channels , *STRUCTURE-activity relationship in pharmacology , *CYTOKINES , *ELECTROPHYSIOLOGY - Abstract
Transient receptor potential melastatin 2 (TRPM2), a Ca 2+ -permeable cationic channel, plays critical roles in insulin release, cytokine production, body temperature regulation and cell death as a reactive oxygen species (ROS) and temperature sensor. However, few TRPM2 inhibitors have been reported, especially TRP-subtype selective inhibitors, which hampers the investigation and validation of TRPM2 as a drug target. To discover novel TRPM2 inhibitors, 3D similarity-based virtual screening method was employed, by which 2,3-dihydroquinazolin-4(1 H )-one derivative H1 was identified as a TRPM2 inhibitor. A series of novel 2,3-dihydroquinazolin-4(1 H )-one derivatives were subsequently synthesized and characterized. Their inhibitory activities against the TRPM2 channel were evaluated by calcium imaging and electrophysiology approaches. Some of the compounds exhibited significant inhibitory activity, especially D9 which showed an IC 50 of 3.7 μM against TRPM2 and did not affect the TRPM8 channel. The summarized structure-activity relationship (SAR) provides valuable insights for further development of specific TRPM2 targeted inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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7. Discovery of new GSK-3β inhibitors through structure-based virtual screening.
- Author
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Dou, Xiaodong, Jiang, Lan, Wang, Yanxing, Jin, Hongwei, Liu, Zhenming, and Zhang, Liangren
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GLYCOGEN synthase kinase-3 , *DRUG use testing , *NEUROPROTECTIVE agents , *STRUCTURE-activity relationships , *CANCER treatment , *MOLECULAR dynamics - Abstract
Glycogen synthase kinase-3β (GSK-3β) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3β inhibitors, and we observed that conserved water molecules of GSK-3β were suitable for virtual screening. We found 14 hits and D1 ( IC 50 of 0.71 μM) were identified. Furthermore, the neuroprotection activity of D1 – D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure–activity relationship suggested that these skeletons were worthy of study as potent GSK-3β inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
8. Angiotensin-I-converting enzyme inhibitory peptides: Chemical feature based pharmacophore generation
- Author
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Wang, Zhanli, Zhang, Saisai, Jin, Hongwei, Wang, Wei, Huo, Jianxin, Zhou, Lishe, Wang, Yongfu, Feng, Fengqin, and Zhang, Liangren
- Subjects
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ANGIOTENSIN converting enzyme , *PEPTIDE synthesis , *MOLECULAR dynamics , *HYDROGEN bonding , *THREE-dimensional imaging , *DATABASES - Abstract
Abstract: A validated 3D pharmacophore model was generated for a series of ACE inhibitory peptides, which consisted of five features (two hydrophobic functions, two hydrogen bond acceptors, and a negative ionizable function). The built model was able to correctly predict the activity of known ACE inhibitors. The model was then used as query to search 3D databases of peptides. Three novel peptides (I, II and III) were synthesized and biologically evaluated in vitro. It appears that the in vitro activity of peptides I, II and III was consistent with their molecular modeling results. Our results provided confidence for the utility of the pharmacophore model to retrieve novel ACE inhibitory peptides with desired biological activity by virtual screening. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
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