Frontiers in Pharmacology
·
2021
·
IF 5.811
Pu Yiqiong,Cai Yiqing,Zhang Qi,Hou Tianling,Zhang Teng,Zhang Tong,Wang Bing
Pinoresinol (PINL) and pinoresinol diglucoside (PDG), two natural lignans found in Eucommia ulmoides Oliv. (Duzhong), have several pharmacological activities. However, there is no report available on their absorption, distribution, metabolism, and elimination (ADME) properties. Given the possible wide spectrum of their application in therapeutic areas, this area should be investigated. This work studied the in vitro ADME properties of PDG and PINL, including their kinetic solubility, permeability across monolayer cells (PAMPA), protein binding, and metabolic stabilities in liver microsomes. The in vivo pharmacokinetic study and in vitro vasorelaxant effects on isolated phenylephrine-induced aortic rings of PINL and PDG were also investigated. It was found that both of their kinetic solubility in PBS (pH 7.4) was greater than 100 μM, indicating that they are both soluble compounds. The permeability investigations (Peff) by PAMPA indicated that PINL had higher permeability than PDG (p < 0.05). Both components represented moderate plasma protein binding activities (average binding rate in human plasma: PINL 89.03%, PDG 45.21%) and low metabolic rate (t1/2 in human liver microsome: PINL 1509.5 min, PDG 1004.8 min). Furthermore, the results of pharmacokinetic studies indicated that PINL might be eliminated less quickly than PDG from the rat plasma, and its cumulative urinary excretion was much lower than that of PDG. The phenylephrine-induced aortic rings demonstrated concentration-dependent vasorelaxation in PDG, PINL, or their combination group. The vasorelaxant effects of PINL were more obvious than those of PDG, whereas the vasorelaxant effect of the combinations was significantly better than that of the single component (p < 0.05). The similarity or difference between PINL and its diglucoside in these pharmaceutical aspects may offer valuable insights into the further exploration of lignans and might contribute to relevant studies involving natural products with similar molecular structure and their glucosides.
研究领域:
药理学
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天然产物化学
·
药物代谢动力学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Xu Gui-Qing,Gong Xiao-Qing,Zhu Ying-Ying,Yao Xiao-Jun,Peng Li-Zeng,Sun Ge,Yang Jian-Xue,Mao Long-Fei
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC50 value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development.
研究领域:
癌症研究
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药物化学
·
药物设计
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生物信息学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Qingxia Zuo,Wanqing Xu,Yanbin Wan,Dongyan Feng,Changsheng He,Cailing Lin,Dongchao Huang,Feng Chen,Liya Han,Qi Sun,Dong Chen,Hongli Du,Lizhen Huang
CRISPR/Cas9 has allowed development of better and easier-to-use ADME models than traditional methods by complete knockout or knock-in of genes. However, gene editing in HepaRG cells remains challenging because long-term monoclonal cultivation may alter their differentiation capacity to a large extent. Here, CRISPR/Cas9 was used to generate a CYP3A4-T2A-luciferase knock-in HepaRG subclone by Cas9-mediated homologous recombination and monoclonal cultivation. The knock-in HepaRG-#9 subclone retained a similar differentiation potential to wildtype HepaRG cells (HepaRG-WT). To further improve differentiation and expand the applications of knock-in HepaRG cells, two optimized differentiation procedures were evaluated by comparison with the standard differentiation procedure using the knock-in HepaRG-#9 subclone and HepaRG-WT. The results indicated that addition of forskolin (an adenylate cyclase activator) and SB431542 (a TGF-β pathway inhibitor) to the first optimized differentiation procedure led to better differentiation consequence in terms of not only the initiation time for differentiation and morphological characterization, but also the mRNA levels of hepatocyte-specific genes. These data may contribute to more extensive applications of genetically modified HepaRG cells in ADME studies.
研究领域:
药理学
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分子生物学
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基因工程
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE REPORTS
·
2019
·Vol. 39
·期 10
·
IF 2.535
Zhou Wei,Chen Ziyi,Zhang Guohao,Liu Zhigang
Maotai liquor is a typical representative of sauce aroma-style flavor liquors and has been considered to be a precious cultural heritage of the oriental spirit culture. Aroma components are largely responsible for the characteristic aroma of liquor. Pyrazine compound is one of the most important categories of aroma components that affect the flavor of Maotai liquor. However, limited information is available regarding the systemic analysis of pyrazine compounds, especially the pharmacological effects of bioactive pyrazine components. Therefore, in the current study, a systemic analysis approach was provided by integrating absorption, distribution, metabolism, and excretion (ADME) screening, target identification, pharmacological evaluation and pathway analysis to explore the pharmacological mechanism of pyrazine compounds in Maotai liquor. As a result, 17 pyrazine components with adequate pharmacokinetic properties were filtered out using ADME models. Thirty eight potential targets of these active compounds were identified through target prediction. The pharmacological evaluation was proposed to uncover the pharmacological effect of pyrazine compounds in Maotai liquor from the holistic perspective. Finally, the pharmacological effects of the pathways perturbed by potential targets were interpreted based on the pathway analysis. Our study lays the foundation for formulating a comprehensive understanding of the pyrazine compounds in Maotai liquor, which would contribute to the development of Chinese liquor.
研究领域:
药理学
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食品科学
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系统生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Zhihui Wang,Yongshuai Yao,Na Liu,Tingting Wei,Xiaoquan Huang,Lingyue Zou,Yuanyuan Hu,Qing Fang,Shujing Guan,Yiru Niu,Xiaoli Wang,Dong Qiao,Congcong Li,Min Chen,Yuying Xue,Tianshu Wu,Ting Zhang,Meng Tang
Cadmium telluride (CdTe) quantum dots (QDs) show great potential for biomedical applications owing to their excellent optical properties. Nevertheless, concerns about their potential neurotoxicity remain unanswered. Here, we conduct a systematic assessment. We study the biodistribution, neurobehavioral effects, and cellular responses in mice after tail vein injection of mercaptopropionic acid–modified CdTe QDs. The QDs display a blood clearance half-life of around 8 h. They mainly accumulate in the liver and kidneys and cross the blood–brain barrier within one hour, with the highest accumulation within the brain regions. Significantly, even though there is transient systemic toxicity, exposure to QDs triggers persistent neuroinflammation and causes substantial impairments in hippocampus-dependent learning and memory. To clarify the underlying mechanisms, we carried out single-cell RNA sequencing on hippocampal tissue. This high-resolution analysis uncovers a coordinated multicellular response, with microglia, oligodendrocyte precursors, and endothelial cells serving as key contributors to inflammatory, oxidative, and cellular stress pathways. These findings clarify the multicellular mechanisms underlying QD-induced neurotoxicity and establish a framework for assessing the neuro-safety of nanomaterials in biomedical settings.
研究领域:
纳米毒理学
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神经科学
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生物医学工程
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免疫学
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药代动力学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2019
·Vol. 84
·期 7
·1949-1956
·
IF 2.081
Wei Zhou,Ziyi Chen,Hui Bao,Guohao Zhang,Zhigang Liu
Maotai liquor is one of the most famous traditional Chinese distilled liquor enjoyed by many people all over the world for its unique production method, impressive liquor quality, and soy sauce-like and roasted aroma style. It is known that aroma characteristics of liquor mainly depend on the aroma compounds. Alcohols as one of the most important categories of aroma components have been determined in Maotai liquor. However, the systemic analysis of alcoholic compounds in liquor is limited, especially the active alcoholic components and their pharmacological effects. Therefore, in this study, a systemic analysis method was proposed by combining in silico absorption, distribution, metabolism, and excretion (ADME) evaluation, target fishing, network pharmacology technology, pathway analysis, and experimental verification to interpret the pharmacological mechanism of alcoholic compounds in Maotai liquor. Finally, 15 compounds with favorable pharmacokinetic profiles were screened through in silico ADME models. Thirty-eight related targets of these active compounds were identified by target prediction method. The network pharmacology and pathway analysis were developed to clarify the pharmacological effect of alcoholic compounds in Maotai liquor at the system and pathway level. Moreover, the key active compounds were validated by in vitro experiments that verified the effectiveness of our methods. Our study provides a novel approach to systematically analyze the pharmacological effect of alcoholic compounds in Maotai liquor, which would be beneficial for promoting the in-depth study of various liquors. Practical Application Maotai liquor is popularly enjoyed in the world for a very long time. However, the systemic analysis of compounds in liquor is limited. Our systematic analysis approach was developed to explore the bioactive ingredients and their related target proteins as well as the pharmacological effects of Maotai liquor. This will provide a new method to understand the pharmacological mechanisms of compounds in various liquors at the systems level, so as to promote the development of liquors and to increase the public awareness of science about alcohol consumption.
研究领域:
药理学
·
系统生物学
·
生物信息学
·
食品科学
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DOI
PubMed
高影响因子
INORGANICA CHIMICA ACTA
·
2025
·
IF 3.2
Yanni Shan,Xudong Fan,Jie Zhang,Xiaoqian Tang,Xinjun Cai,Chongyang Wu
A series of mixed-ligand ruthenium (II) complexes [RuCl(ecz)(P P)(N N)]PF 6 ( 3a–3f ) were synthesized with econazole (ecz) as bioactive ligand, alongside phosphine (PPh 3 , dppb, dppf) and nitrogen (bipy, phen) donors. Characterized by elemental analysis, FTIR, NMR, UV–vis, HRMS, TGA, and X-ray diffraction, they showed stable distorted octahedral geometry. Biological evaluations demonstrated that most complexes (particularly 3c ) exhibited potent and selective cytotoxicity against A549, U251, and LLC cancer cells, with superior anticancer activity to cisplatin while showing lower toxicity toward normal cells. Mechanistically, complex 3c induces cell death via dual pathways of cell membrane disruption and intracellular ROS accumulation. In antimicrobial assays, most complexes enhanced econazole's activity, with 3 f showing notable improvements that include efficacy against econazole-resistant S. aureus and heightened antifungal activity against C. albicans . In silico ADME studies revealed favorable bioavailability and CYP3A4 non-inhibition in 3b, 3c, 3e, 3 f, supporting their potential as multi-functional metallodrug candidates.
研究领域:
肿瘤学
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药理学
·
药物化学
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微生物学
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金属药物化学
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分子药理学
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转化医学
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产品关联
DOI
高影响因子
BMC Chemistry
·
2026
·
IF 5.1
Wang Hu,Shi Hua,Guo Pengxiao,Zhang Xia,Zhou Yadong,Wang Renshu,Yin Chaochuang,Zhu Yangyang
In the present study, two Cu(II) complexes incorporating a Schiff base ligand, termed CuSBCs, were synthesized and subjected to structural characterization. The complexes are denoted as [Cu(C 10 H 8 NO 4 F)(C 10 H 9 N 3 )]·H 2 O ( C1 ) and [Cu(C 10 H 8 NO 4 F)(C 12 H 12 N 2 )]·H 2 O·CH 3 OH ( C2 ), featuring the Schiff base ligand (SBL, C 10 H 8 NO 4 F) and distinct auxiliary ligands, specifically 2,2’-dipyridylamine and 5,5’-dimethyl-2,2’-bipyridine. Within these two complexes, the central Cu(II) ion exhibits pentacoordination, binding to ONO donor sites of the SBL as well as two nitrogen donor atoms provided by the auxiliary ligand, yielding a distorted square pyramidal geometry. Theoretical computations for both complexes were performed using density functional theory (DFT) with the B3LYP functional via the Gaussian 16 program. The computational results are in good agreement with experimental observations. Notably, both complexes exhibited significant inhibitory activity against jack bean urease (UA), with C1 (IC 50 = 4.79 ± 0.77 µM) outperforming C2 (IC 50 = 6.83 ± 1.19 µM) and the reference inhibitor acetohydroxamic acid (AHA). Molecular docking (MOD) and molecular dynamics (MD) simulations reveal that the superior activity of C1 originates from its better steric matching and more stable interactions with the enzyme active site, providing structural evidence for the experimental activity trend. In addition, ADME predictions indicated that both complexes possess favorable drug-like properties and promising bioavailability. These findings highlight the promising therapeutic potential of Cu(Ⅱ) Schiff base complexes as UA inhibitors. Graphical
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DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2021
·
IF 3.196
Meng Ding,Lei Xu,Yumeng Zhang,Wei Li,Yuqing Zhao
20( R )-25-methoxyl-dammarane-3 β ,12 β ,20-triol (CN Patent: 201,010,107,476.7, AD-1) is a promising antitumor compound, was isolated from total hydrolyzed saponins extracted from Panax notoginseng leaves. A sensitive and rapid method for the simultaneous detection of AD-1 and its 8 major metabolites in rat feces was developed in this study. AD-1 (20 mg/kg) was orally administered to male rats by gastric intubation. Then, the feces samples were collected. After addition of internal standard (Mifepristone), feces samples were pretreated by protein precipitation followed by liquid-liquid extraction. Chromatographic separation was performed on an Angela C 18 column with gradient elution using a mobile phase composed of acetonitrile and water (containing 5 mM ammonium acetate) at a flow rate of 0.3 mL/min. The analytes were detected without any interference from the multiple reaction monitoring (MRM) mode using positive electrospray ionization. Calibration curves offered satisfactory linearity ( r > 0.995) within the determined ranges. Both intra-day and inter-day variances were lower than 15%, and the accuracy was within 85–115%. The fecal excretion recoveries of AD-1 (M0), metabolite 1 (M1), M2, M3, M4, M5, M6, M7 and M8 were 41.36%, 0.62%, 6.20%, 0.50%, 6.99%, 2.07%, 1.86%, 0.41% and 0.29%, respectively. The observed excretion profiles for AD-1 and its metabolites after oral administration are helpful to understand the poor oral bioavailability of AD-1, and will aid further investigations of AD-1 as a pharmacologically active component. Moreover, the in silico ADME (Absorption, Distribution, Metabolism, Excretion) predictions indicated that the metabolites were nontoxic and present passive gastrointestinal absorption. In previous studies, we found that M5, a metabolite of AD-1, has strong cytotoxicity against ovarian cancer cells. Further molecular docking studies showed that the most potent metabolite, M5, effectively binds to poly ADP-ribose polymerase-1 (PARP-1), which may provide novel solutions for treating ovarian cancer.
研究领域:
药理学
·
药物代谢动力学
·
计算生物学
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产品关联
DOI
高影响因子
CHEMISTRY & BIODIVERSITY
·
2023
·Vol. 20
·期 8
·e202300942
·
IF 2.9
Jiayi Ou,Weiyun Tan,Gong Chen,Xianjing Yang,Yan Luo,Xiaobao Jin,Lianbao Ye
Glioma is the most common brain tumor and its treatment options are limited. Abietic acid and dehydroabietic acid are tricyclic diterpenoid oxygen compounds with strong lip solubility and anti-glioma activity. In this study, novel rosin diterpenoid derivatives were designed and synthesized using abietic acid and dehydrogenated abietic acid as lead compounds and their activities against T98G, U87MG, and U251 cells were evaluated by CCK-8 methods. The in vivo activity of compounds with stronger activity in vitro was preliminarily studied through the Zebrafish model. The results showed that the IC 50 values of B6 , B8 , B10 , and B12 were 11.47 to 210.6 μM, which were exhibited higher antiproliferative potency against T98G, U87MG, and U251. The scratch experiment showed that B12 inhibited the migration of T98G in a time-dependent and concentration-dependent manner. The results of in vivo activity further explained that B12 could inhibit the proliferation of the T98G. The pKa values of B6 , B8 , B10 , and B12 were 7.17 to 7.35, which were within the ideal range of glioma drugs. The ADME predictions indicated that these derivatives could pass through the blood-brain barrier. In addition, molecular docking primarily explained interaction between compounds and protein. These results suggested that B12 should be a promising candidate that merits further attention in the development of anti-glioma drugs. Graphical
研究领域:
药理学
·
肿瘤学
·
药物化学
·
药物发现
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
·
2017
·
IF 1.754
Xiuqing Zhang,Ting Liu,Xiaohui Fan,Ni Ai
In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP. Herein poor discriminative performance on BBB permeability of NP are first confirmed using internal constructed and previously published drug-derived computational models, which warrants the need for NP-oriented modeling. Then a quantitative structure−property relationship (QSPR) study on a NP dataset was carried out using four different machine learning methods including support vector machine, random forest, Naïve Bayes and probabilistic neural network with 67 selected features. The final consensus model was obtained with approximate 90% overall accuracy for the cross-validation study, which is further taken to predict passive BBB permeability of a large dataset consisting of over 10,000 compounds from traditional Chinese medicine (TCM). For 32 selected TCM molecules, their predicted BBB permeability were evaluated by in vitro parallel artificial membrane permeability assay and overall accuracy for in vitro experimental validation is around 81%. Interestingly, our in silico model successfully predicted different BBB permeation potentials of parent molecules and their known in vivo metabolites. Finally, we found that the lipophilicity, the number of hydrogen bonds and molecular polarity were important molecular determinants for BBB permeability of NP. Our results suggest that the consensus model proposed in current work is a reliable tool for prioritizing potential CNS active NP across the BBB, which would accelerate their development and provide more understanding on their mechanisms, especially those with pharmacologically active metabolites.
研究领域:
药物化学
·
计算生物学
·
中药学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2024
·
IF 2.7
Chunying Du,Hua Yin,Aowei Xie,Junhong Yu,Yifan Wang,Fengli Yao,Siyu Zhang,Yidan Zhang,Lu Liu,Peng Wang,Jianjun Dong,Ximing Xu
Hyperuricemia is mainly caused by insufficient renal urate excretion. Urate transporter 1 (URAT1), an organic anion transporter, is the main protein responsible for urate reabsorption. In this study, we utilized artificial intelligence-based AlphaFold2 program to construct URAT1 structural model. After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. Combining pharmacophore modeling, molecular docking, MM/GBSA calculation and ADME prediction, 25 flavonoids were selected from the natural products database containing 10,968 molecules. Then, a model of HEK-293T cells overexpressing URAT1 was constructed, and the inhibitory activity to URAT1 of 25 flavonoids was evaluated by measuring their effect on cellular uptake of 6-carboxyfluorescein (6-CFL). Fisetin, baicalein, and acacetin showed the best activity with IC50 values of 12.77, 26.71, and 57.30 µM, respectively. Finally, the structure-activity relationship of these three flavonoids was analyzed by molecular docking and molecular dynamics simulations. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5’ in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma
研究领域:
药理学
·
生物信息学
·
分子生物学
·
药物发现
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）