Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 268
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioinformatics ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32428219

RESUMO

MOTIVATION: Identifying compound-protein interaction (CPI) is a crucial task in drug discovery and chemogenomics studies, and proteins without three-dimensional (3D) structure account for a large part of potential biological targets, which requires developing methods using only protein sequence information to predict CPI. However, sequence-based CPI models may face some specific pitfalls, including using inappropriate datasets, hidden ligand bias, and splitting datasets inappropriately, resulting in overestimation of their prediction performance. RESULTS: To address these issues, we here constructed new datasets specific for CPI prediction, proposed a novel transformer neural network named TransformerCPI, and introduced a more rigorous label reversal experiment to test whether a model learns true interaction features. TransformerCPI achieved much improved performance on the new experiments, and it can be deconvolved to highlight important interacting regions of protein sequences and compound atoms, which may contribute chemical biology studies with useful guidance for further ligand structural optimization. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. AVAILABILITY AND IMPLEMENTATION: https://github.com/lifanchen-simm/transformerCPI.

2.
Curr Pharm Des ; 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32338210

RESUMO

BACKGROUND: Enhancing compound biological activity is the central task for lead optimization in small molecule drug discovery. However, it is laborious to perform many iterative rounds of compound synthesis and bioactivity test. To address the issue, it is high-demanding to develop high quality in silico bioactivity prediction approaches, to prioritize those more active compound derivatives and reduce the trial-and-error process. METHODS: Two kinds of bioactivity prediction models based on a large-scale structure activity relationship (SAR) database were constructed. The first one is based on the similarity of substituents and realized by matched molecular pair analysis, including SA, SA_BR, SR, and SR_BR. The second one is based on SAR transferability and realized by matched molecular series analysis, including Single MMS pair, Full MMS series, and Multi single MMS pairs. Moreover, we also defined the application domain of models by using the distance-based threshold. RESULTS: Among seven individual models, Multi single MMS pairs bioactivity prediction model showed the best performance (R2 = 0.828, MAE = 0.406, RMSE = 0.591), and the baseline model (SA) produced the most inferior prediction accuracy (R2 = 0.798, MAE = 0.446, RMSE = 0.637). The predictive accuracy could further be improved by consensus modeling (R2 = 0.842, MAE = 0.397 and RMSE = 0.563). CONCLUSION: An accurate prediction model for bioactivity was built with consensus method, which was superior to all individual models. Our model should be a valuable tool for lead optimization.

3.
J Integr Med ; 18(3): 229-241, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32307268

RESUMO

OBJECTIVE: Lung-toxin Dispelling Formula No. 1, referred to as Respiratory Detox Shot (RDS), was developed based on a classical prescription of traditional Chinese medicine (TCM) and the theoretical understanding of herbal properties within TCM. Therapeutic benefits of using RDS for both disease control and prevention, in the effort to contain the coronavirus disease 2019 (COVID-19), have been shown. However, the biochemically active constituents of RDS and their mechanisms of action are still unclear. The goal of the present study is to clarify the material foundation and action mechanism of RDS. METHODS: To conduct an analysis of RDS, an integrative analytical platform was constructed, including target prediction, protein-protein interaction (PPI) network, and cluster analysis; further, the hub genes involved in the disease-related pathways were identified, and the their corresponding compounds were used for in vitro validation of molecular docking predictions. The presence of these validated compounds was also measured in samples of the RDS formula to quantify the abundance of the biochemically active constituents. In our network pharmacological study, a total of 26 bioinformatic programs and databases were used, and six networks, covering the entire Zang-fu viscera, were constructed to comprehensively analyze the intricate connections among the compounds-targets-disease pathways-meridians of RDS. RESULTS: For all 1071 known chemical constituents of the nine ingredients in RDS, identified from established TCM databases, 157 passed drug-likeness screening and led to 339 predicted targets in the constituent-target network. Forty-two hub genes with core regulatory effects were extracted from the PPI network, and 134 compounds and 29 crucial disease pathways were implicated in the target-constituent-disease network. Twelve disease pathways attributed to the Lung-Large Intestine meridians, with six and five attributed to the Kidney-Urinary Bladder and Stomach-Spleen meridians, respectively. One-hundred and eighteen candidate constituents showed a high binding affinity with SARS-coronavirus-2 3-chymotrypsin-like protease (3CLpro), as indicated by molecular docking using computational pattern recognition. The in vitro activity of 22 chemical constituents of RDS was validated using the 3CLpro inhibition assay. Finally, using liquid chromatography mass spectrometry in data-independent analysis mode, the presence of seven out of these 22 constituents was confirmed and validated in an aqueous decoction of RDS, using reference standards in both non-targeted and targeted approaches. CONCLUSION: RDS acts primarily in the Lung-Large Intestine, Kidney-Urinary Bladder and Stomach-Spleen meridians, with other Zang-fu viscera strategically covered by all nine ingredients. In the context of TCM meridian theory, the multiple components and targets of RDS contribute to RDS's dual effects of health-strengthening and pathogen-eliminating. This results in general therapeutic effects for early COVID-19 control and prevention.


Assuntos
Antivirais/química , Betacoronavirus/química , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Pneumonia Viral/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Espectrometria de Massas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Mapas de Interação de Proteínas , Proteínas não Estruturais Virais/química
4.
Artigo em Inglês | MEDLINE | ID: mdl-32277730

RESUMO

Placobranchus ocellatus is well known to produce diverse and complex γ-pyrone polypropionates. In this study, the chemical investigation of P. ocellatus from the South China Sea led to the discovery and identification of ocellatusones A-D, a series of racemic non-γ-pyrone polyketides with novel skeletons, characterized by a bicyclo[3.2.1]octane (1, 2), a bicyclo[3.3.1]nonane (3) or a mesitylene-substituted dimethylfuran-3(2H)-one core (4). Extensive spectroscopic analysis, quantum chemical computation, chemical synthesis, and/or X-ray diffraction analysis were used to determine the structure and absolute configuration of the new compounds, including each enantiomer of racemic compounds 1-4 after chiral HPLC resolution. An array of new and diversity-generating rearrangements is proposed to explain the biosynthesis of these unusual compounds based on careful structural analysis and comparison with six known co-occurring γ-pyrones (5-10). Furthermore, the successful biomimetic semisynthesis of ocellatusone A (1) confirmed the proposed rearrangement through an unprecedented acid induced cascade reaction.

5.
J Ethnopharmacol ; 256: 112795, 2020 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-32224197

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthus ilicifolius L. has been used as a folk medicine in the treatment of acute and chronic hepatitis in China for a long time. Phenylethanoid glycosides are one of main components in A. ilicifolius L. AIM OF THE STUDY: The aim of present study was to assess the hepatoprotective activities of total phenylethanoid glycosides from A. ilicifolius L. (APhGs) against carbon tetrachloride (CCl4)-induced liver injury in vivo and in vitro. MATERIALS AND METHOD: The APhGs was separated by resin column chromatography. The purity of total phenylethanoid glycosides was determined by UV-Vis spectrophotometry using acteoside as a standard. The hepatoprotective activities of APhGs against CCl4-induced liver injury were performed on experimental mice and L-02 hepatocytes. Moreover, the antioxidant activities of APhGs were tested in vitro. RESULTS: The results showed that pre-administration of APhGs to mice decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum, and improved superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) level in serum and liver tissue induced by CCl4. Specifically, the SOD activities of APhGs-H and APhGs-M treatment groups were stronger than that of silymarin treatment group. The protective activities of APhGs were confirmed by histopathological results. Moreover, immunohistochemical analysis showed that APhGs could remarkably down-regulate the protein expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). In vitro experiment, APhGs was observed to increase L-02 hepatocyte viability against CCl4-induced hepatotoxicity. In addition, antioxidation assays revealed that APhGs showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, and ferric reducing ability. CONCLUSION: Overall, total phenylethanoid glycosides from A. ilicifolius L. displayed promising hepatoprotective effects. These results offer a support for the medicine uses of A. ilicifolius L.

6.
Oncol Rep ; 43(6): 1928-1944, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236631

RESUMO

Breast cancer is one of the most common malignancies that threaten the health of women. Although there are a few chemotherapies for the clinical treatment of breast cancer, these therapies are faced with the problems of drug­resistance and metastasis. Drug combination can help to reduce the adverse side effects of chemotherapies using single drugs, and also help to overcome common drug­resistance during clinical treatment of breast cancer. The present study reported the synergistic effect of the heat shock protein 90 inhibitor 17­AAG and the histone deacetylase 6 inhibitor Belinostat in triple­negative breast cancer (TNBC) MDA­MB­231 cells, by detection of proliferation, apoptosis and cell cycle arrest following treatment with this combination. Subsequently, RNA sequencing (RNA­seq) data was collected and analyzed to investigate the synergistic mechanism of this combination. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways revealed by RNA­seq data analysis, a wound­healing assay was used to investigate the effect of this combination on the migration of MDA­MB­231 cells. Compared with treatment with 17­AAG or Belinostat alone, both the viability inhibition and apoptosis rate of MDA­MB­231 cells were significantly enhanced in the combination group. The combination index values were <1 in three concentration groups. Revealed by the RNA­seq data analysis, the most significantly enriched KEGG pathways in the combination group were closely associated with cell migration. Based on these findings, the anti­migration effect of this combination was investigated. It was revealed that the migration of MDA­MB­231 cells was significantly suppressed in the combination group compared with in the groups treated with 17­AAG or Belinostat alone. In terms of specific genes, the mRNA expression levels of TEA domain family proteins were significantly decreased in the combination group, whereas the phosphorylation of YY1 associated protein 1 and modulator of VRAC current 1 was significantly enhanced in the combination group. These alterations may help to explain the anti­migration effect of this combination. Belinostat has already been approved as a treatment for T­cell lymphoma and 17­AAG is undergoing clinical trials. These findings could provide a beneficial reference for the clinical treatment of patients with TNBC.

7.
Phytochemistry ; 174: 112337, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32163787

RESUMO

Four undescribed sulfur-containing indole alkaloids, isatisindigoticanines H, I and isatindigosides F, G along with three known analogues were obtained from Isatis tinctoria L. roots. Isatisindigoticanines H and I contained an unusual 1-(thiazol-4-yl)butane-1,2,3,4-tetraol moiety while isatindigosides F and G possessed a new 3-[3-(1H-indole-2-yl)azet-2-yl]-1H-indole skeleton. The putative biosynthetic pathways of isatisindigoticanines H, I and isatindigosides F, G are proposed. The isolated compounds showed nitric oxide inhibitory effects with IC50 values ranging from 4.3 to 70.3 µM.


Assuntos
Isatis , Alcaloides Indólicos , Estrutura Molecular , Óxido Nítrico , Raízes de Plantas , Enxofre
8.
J Med Chem ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32191458

RESUMO

Aldehyde oxidase (AOX) is a drug metabolizing molybdo-flavoenzyme that has gained increasing attention because of contribution to the biotransformation in phase I metabolism of xenobiotics. Unfortunately, the intra- and interspecies variations in AOX activity and lack of reliable and predictive animal models make evaluation of AOX-catalyzed metabolism prone to be misleading. In this study, we developed an improved computational model integrating both atom-level and molecule-level features to predict whether a drug-like molecule is a potential human AOX (hAOX) substrate and to identify the corresponding sites of metabolism. Additionally, we combined the proposed computational strategy and in vitro experiments for evaluating the metabolic property of a series of epigenetic-related drug candidates still in the early stage of development. In summary, this study provides an improved strategy to evaluate the liability of molecules toward hAOX and offers useful information for accelerating the drug design and optimization stage.

9.
Chem Commun (Camb) ; 56(23): 3441-3444, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32101183

RESUMO

α-Diazo quinones were applied in an Ir(iii)-catalyzed direct C-H functionalization assisted by N-phenylacetamide for the construction of highly functionalized 2-hydroxy-2'-amino-1,1'-biaryl scaffolds in good to excellent yields. This strategy features operational simplicity, atom- and step-economy and high efficiency.

10.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936532

RESUMO

A traceless approach to quinolin-4(1H)-one scaffolds through Rh(III)-catalyzed redox-neutral [3+3] cyclization of N-nitrosoanilines with cyclopropenones has been achieved. This protocol features short reaction time and atom-economical combination without extra additives, which can be further applied in the construction of privileged heterocyclic compounds in pharmaceutical chemistry.

11.
J Biomol Struct Dyn ; 38(4): 975-984, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30843765

RESUMO

Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis, and protein targets for the development of anti-cancer drugs. Cellular inhibitor of apoptosis protein-1 (cIAP1) is an important member of IAPs. Peptides or small-molecular antagonists can induce the dimerization, auto-ubiquitination, and proteasomal degradation of the cellular inhibitor of apoptosis protein-1 (cIAP1). While in the absence of antagonists, several mutations of the cIAP1 protein also lead to its dimerization and auto-ubiquitination. Even though the crystal structure of cIAP1 protein has been determined, the intrinsic mechanism of its dimerization remains unexplored. Accumulating evidence indicated that intrinsic conformational change existed during the binding of antagonists with cIAP1 protein, or introduction of mutations. To reveal this intrinsic conformational change, molecular dynamics simulations at microsecond scale were applied for the wild-type and mutant-type cIAP1 proteins. Compared to the crystal structure, significant conformational change was observed during the simulations, which could explain the importance of previously identified key mutations. To validate these findings revealed by our simulations, a new mutation D303A was constructed and the following native polyacrylamide gel electrophoresis (native-PAGE) assay observed a proportion of spontaneous dimerization, in comparison with the wild-type control. Taken together, these computational and experimental results revealed the intrinsic conformational change of cIAP1, which could not only explain previously identified key mutations, but also be exploited for further design and development of anti-tumor compounds that target the cIAP1 protein.Communicated by Ramaswamy H. Sarma.

12.
Angew Chem Int Ed Engl ; 59(6): 2429-2439, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31782597

RESUMO

Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti-inflammation in LPS-induced neuroinflammatory mice model and cerebral ischemic injury through anti-neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti-inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti-neuroinflammatory effect in vitro and in vivo by inhibiting PKM2-mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation-related diseases.

13.
Front Chem ; 7: 763, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781545

RESUMO

The zoanthid-derived fungus Cochliobolus lunatus (TA26-46) has been proven to be a source of bioactive 14-membered resorcylic acid lactones (RALs). In the present study, chemical epigenetic manipulation was applied to this fungal strain with a DNA methyltransferase inhibitor resulting in the significant changes of the secondary metabolites. Cultivation of C. lunatus (TA26-46) with 10 µM 5-azacytidine in Czapek-Dox liquid medium led to the isolation of new types of metabolites, including two α-pyrones, cochliobopyrones A (1) and B (2), along with three isocoumarins (3-5) and one chromone (6). The planar structures of the new compounds (1-2) were elucidated by comprehensive analyses of NMR and HRESIMS data. Their challenging relative configurations were established by a combination of acetonide reaction, coupling constants and NOESY correlations analysis, and DP4+ probability calculation. Their absolute configurations were determined by comparing with the ECD calculation data of the fragment molecules, 6-(1,2-dihydroxypropyl)-4-methoxy-2H-pyran-2-ones. It is the first time to obtain α-pyrone compounds with the epoxy ring or bromine atom on the seven-numbered side chain. It could be concluded that chemical epigenetic agents could induce C. lunatus to produce new types of secondary metabolites differing from its original products (RALs).

14.
Molecules ; 24(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703370

RESUMO

As our ongoing research project on Ban Lan Gen (Isatis tinctoria roots), a total of 23 alkaloids were obtained. Compounds 1 and 2 contain an unusual C-C bond between the 2(1H)-quinolinone moiety and the phenol moiety and between the 2(1H)-quinolinone moiety and the 1H-indole moiety, respectively. Compound 3 possesses an unusual carbon skeleton and its putative biosynthetic pathway was discussed, and Compound 23 was deduced as a new indole alkaloid glycoside. Compounds 4-7 were identified as four new natural products by extensive spectroscopic experiments. Additionally, the anti-inflammatory activity was assessed based on nitric oxide (NO) production using Lipopolysaccharide-stimulated RAW264.7 macrophages. Compounds 9, 15, and 17 showed inhibitory effects with IC50 values of 1.2, 5.0, and 74.4 µM.

15.
Theranostics ; 9(26): 8344-8361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754401

RESUMO

High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available. Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative. As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury. Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets. A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo. For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485. A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy. Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro. Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice. Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks. Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment. Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury. Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment. We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro. Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases.

16.
Eur J Med Chem ; 184: 111767, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622854

RESUMO

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ±â€¯19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.


Assuntos
Descoberta de Drogas , Ácido Palmítico/antagonistas & inibidores , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Compostos de Vinila/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HEK293 , Humanos , Estrutura Molecular , Ácido Palmítico/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Fatores de Transcrição/metabolismo , Compostos de Vinila/síntese química , Compostos de Vinila/química
17.
J Ethnopharmacol ; : 112260, 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31577937

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria barbata D. Don (S. barbata) is a well-known perennial herb that is used in traditional Chinese and Korean medicine. In China, it is known as Ban Zhi Lian, while in Korea, it is known as Banjiryun. In the Traditional Chinese Medicine (TCM) system, S. barbata has heat-clearing and detoxifying properties (Qingre Jiedu in Chinese). AIM OF THE REVIEW: To provide a systematic review on current multifaceted understanding of S. barbata, with particular emphasis on the correlation between its traditional applications and pharmacological activities. MATERIALS AND METHODS: All available S. barbata-related information from internet databases, including PubMed, Science Direct, Elsevier, China National Knowledge Internet, and Google Scholar (up to October 2018) were searched. Additional information was gathered from classical books on Chinese Herbals, Chinese Pharmacopoeia, and so on. RESULTS: In the TCM system, S. barbata is mainly prescribed for its heat-clearing and detoxifying effects. More than 203 compounds have been isolated and identified from this herb, with neo-clerodane diterpenoids and flavonoids as the main compounds. Most neo-clerodanes have been demonstrated to have cytotoxic effects against different cancer cell types in vitro. The S. barbata extracts exhibited anti-inflammatory, anti-microbial, antitumor, and other pharmacological activities. To add, flavonoids, including wogonin, baicalein, apigenin, naringenin, and scutellarin, were identified as the key to quality control. CONCLUSIONS: The heat-clearing effects of S. barbata could be attributed to its anti-inflammatory and hepatoprotective activities, whereas its detoxifying effects might be due to the anti-microbial functions of neo-clerodane diterpenoids and flavones. S. barbata may display anti-tumor effects and through active ingredient analysis, neo-clerodane diterpenoids are suggested to be its representative compounds. Overall, many pre-clinical studies have been conducted but very little concrete evidences are available on its specific effects, which are of therapeutic relevance.

18.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470525

RESUMO

Five pairs of alkaloid enantiomers (1a/1b-5a/5b) were obtained from Isatis indigotica (I. indigotica) roots. Among them, 1a/1b, 2a/2b and 3a/3b were determined as three pairs of new alkaloid enantiomers. Their structures were elucidated by physicochemical properties and spectroscopic methods. The absolute configurations were deduced by comparison of their experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra, as well as by single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation. Alkaloids 1a and 1b possess an unpresented carbon skeleton and their putative biosynthetic pathways are discussed. Moreover, all of the alkaloids were tested for their nitric oxide (NO) inhibitory effects in RAW 264.7 cells, and 4a and 4b showed inhibitory effects with IC50 values of 76.97 µM and 65.88 µM, respectively.


Assuntos
Alcaloides/química , Anti-Inflamatórios/química , Isatis/química , Lipopolissacarídeos/antagonistas & inibidores , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Relação Dose-Resposta a Droga , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Raízes de Plantas/química , Células RAW 264.7 , Estereoisomerismo
19.
Am J Chin Med ; 47(6): 1193-1221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488038

RESUMO

Veronica is the largest genus in the flowering plant family Plantaginaceae and comprises approximately 500 species. The genus was formerly placed in the Scrophulariaceae family, some species of which have been used in traditional medicine for the treatment of influenza, respiratory diseases, hemoptysis, laryngopharyngitis, cough, hernia, cancer, edema, and wounds. This review comprehensively summarizes the current information on the traditional uses, phytochemistry, and pharmacology of the genus Veronica on the basis of articles published from 1970 to 2018. More than 260 compounds have been isolated, and chemotaxonomic investigations of Veronica have revealed that iridoid glucosides - including aucubin, catalpol, and 6-O-catalpol derivatives - are characteristic of this genus. Modern pharmacological studies and clinical practice have demonstrated that extracts or monomeric compounds from Veronica have several pharmacological actions, such as anti-inflammatory, anti-oxidative, anticancer, antibacterial, anti-angiogenic, antineurodegenerative, neuroprotective, and hepatoprotective effects both in vivo and in vitro.


Assuntos
Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Veronica/química , Inibidores da Angiogênese , Animais , Antibacterianos , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Antioxidantes , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Glucosídeos Iridoides/química , Medicina Tradicional , Conformação Molecular , Fármacos Neuroprotetores , Fitoterapia , Terpenos/síntese química , Terpenos/isolamento & purificação , Terpenos/farmacologia
20.
Front Pharmacol ; 10: 924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507420

RESUMO

Scoring functions play an important role in structure-based virtual screening. It has been widely accepted that target-specific scoring functions (TSSFs) may achieve better performance compared with universal scoring functions in actual drug research and development processes. A method that can effectively construct TSSFs will be of great value to drug design and discovery. In this work, we proposed a deep learning-based model named DeepScore to achieve this goal. DeepScore adopted the form of PMF scoring function to calculate protein-ligand binding affinity. However, different from PMF scoring function, in DeepScore, the score for each protein-ligand atom pair was calculated using a feedforward neural network. Our model significantly outperformed Glide Gscore on validation data set DUD-E. The average ROC-AUC on 102 targets was 0.98. We also combined Gscore and DeepScore together using a consensus method and put forward a consensus model named DeepScoreCS. The comparison results showed that DeepScore outperformed other machine learning-based TSSFs building methods. Furthermore, we presented a strategy to visualize the prediction of DeepScore. All of these results clearly demonstrated that DeepScore would be a useful model in constructing TSSFs and represented a novel way incorporating deep learning and drug design.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA