RESUMEN

This article addresses the synthesis of Fe3+doped TiO2nanoparticles with variations of molar concentrations of Fe3+and their adequate use as potential photocatalysts for Photocatalysis applications. Synthesized photocatalysts were characterized thoroughly by different analytical techniques in terms of morphological, chemical, structural, crystalline, optical, electronic structure, surface area etc properties. The occurrence of red shift phenomenon of the energy band gap attributes to the transfer of charges and transition between the d electrons of dopant and conduction band (CB) or valence band (VB) of TiO2. The doping of Fe3+ions generates more trap sites for charge carriers with the surface trap sites. Thorough experimental conclusions revealed that the Fe3+ions necessarily regulate the catalytic property of TiO2nanomaterial. The obtained total degradation efficiency rate of Methylene Blue (MB) was 93.3% in the presence of 0.1 M Fe3+in the host material and for Malachite Green Oxalate the efficiency was 100% in the presence of 0.05 M and 0.1 M Fe3+in the host material. In both the cases the total visible light irradiation time was 90 min. The adsorption properties of the photocatalysts have been also performed in a dark for 90 min in the presence of MB dye. However, till now there are hardly reported photocatalysts which shows complete degradation of these toxic organic dyes by visible light driven photocatalysis. of potential values of valence and conduction band shows the production of active oxidizing species for hydrogen yield and the possible mechanism of the Schottky barrier has been proposed. A schematic diagram of visible light driven Photocatalysis has been pictured showing degradation activity of Fe3+-TiO2catalysts sample.

RESUMEN

The Taiwan Adverse Drug Reaction Reporting System for Herbal Medicine (TADRRS-HM) has systematically documented suspected adverse events from adverse drug reaction (ADR) reports from 1998 (prior to its formal establishment in 2001) and evaluates safety profiles of herbal medicines. This article describes findings from 2079 ADR reports filed between 1998 and 2016: 941 reports involved single herbs and 87 involved folk herbals; 842 were generated from clinical trials, while 209 ADR reports involving foods, health foods, dietary supplement foods and herbal cuisine were grouped as Other. Severity assessments using the Modified Hartwig and Siegel scale classified 72.4% of ADRs as mild, 17.4% as moderate and 6.5% as severe. System Organ Class classification of the ADRs identified gastrointestinal system disorders as the most common (33.4%), followed by skin and subcutaneous tissue disorders (21.2%). The TADRRS-HM records indicate that herbal medicines may cause a wide range of ADRs. Aconiti Radix, Xiao-Qing-Long-Tang, and Datura suaveolens were the most commonly reported single herb, herbal formula, and folk herbal, respectively. The data indicate that herbal medicines may cause a wide range of ADRs. This system will confer long-term benefits for the development of Taiwan's herbal medicines adverse reaction database and facilitate epidemiological analysis.

Asunto(s)

Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Medicina de Hierbas/métodos , Fitoterapia/efectos adversos , Plantas Medicinales/efectos adversos , Enfermedades de la Piel/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Farmacovigilancia , Enfermedades de la Piel/etiología , Taiwán , Factores de Tiempo

RESUMEN

In previous research, a series of cytotoxic anticancer analogues related to 2-acylamino-1,4-naphthoquinone derivatives has been demonstrated. As microtubule plays an important role in many essential cellular processes such as mitosis, tubulin is an important target of anticancer drug. This study performed molecular docking simulation, pharmacophore model, comparative force field analysis model and comparative similarity indices analysis model to investigate the relationship between inhibitory activities and the properties of compounds, in order to further progress the development of cytotoxic anticancer analogues. These compounds have common H-bond interactions with key residues Lys254 and Lys352, but compounds with large R2 substituent have different docking poses than compounds with small R2 substituent. Some of derivatives such as compound 18 formed the H-bonds with residue Lys254 using the oxygen atoms in R1 substituent and formed π-cation interactions with residue Lys352 using phenyl moiety of 1,4-naphthoquinone. The R1 substituent of these compounds preferred to have disfavoured hydrophobic fields and favourable space towards the direction of residue Asn258, while the R2 substituent of these compounds preferred to have about 2-3 carbon chain length hydrophobic substituent towards the direction of residues Ala316 and Lys352. These results offer some beneficial advices for further study in anticancer drug development process.

Asunto(s)

Antineoplásicos/química , Melanoma/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Naftoquinonas/química , Proteínas de Neoplasias/química , Tubulina (Proteína)/química , Antineoplásicos/uso terapéutico , Humanos , Naftoquinonas/uso terapéutico

RESUMEN

Although the regulation of the enzyme-like activities of nanozymes has stimulated great interest recently, the exploration of modulators makes it possible to enhance the catalytic performance of nanozymes, though doing so remains a big challenge. Herein, we systemically studied the effects of fluorescence quenchers on the peroxidase-like activity of bovine serum albumin-stabilized gold nanoclusters (BSA-AuNCs) based on photoinduced electron transfer (PET). We found that PET quenchers can not only quench the fluorescence of BSA-AuNCs but also regulate their intrinsic peroxidase-like activity. Importantly, both BSA and human serum albumin (HSA) could enhance the peroxidase-like activity of Cu2+, which provided a new sensing platform for distinguishing BSA and HSA from other thiol-containing biomolecules. The PET quenchers could also manipulate the peroxidase-like activity of polyvinylpyrrolidone-stabilized gold nanoparticles (PVP-AuNPs), which exhibited some opposite results between PVP-AuNPs and BSA-AuNCs. The opposite effects on BSA-AuNCs and PVP-AuNPs were speculated to highly depend on their surface properties. Our findings offer an efficient strategy for tuning the peroxidase-like activities of gold-based nanozymes.

RESUMEN

BACKGROUND AND PURPOSE: Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad-spectrum pharmacological properties including anti-microbial, anti-diabetic and anti-tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti-angiogenic mechanisms of a novel 2-aminobenzimidazole-based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor. EXPERIMENTAL APPROACH: Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF-A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti-angiogenic effects of Jzu 17. KEY RESULTS: Jzu 17 inhibited VEGF-A-induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF-A-induced microvessel sprouting ex vivo and attenuated VEGF-A- or tumour cell-induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR-2 and its downstream signalling molecules in VEGF-A-stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR-2 with high affinity. CONCLUSIONS AND IMPLICATIONS: Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF-A-VEGFR-2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis-related diseases.

Asunto(s)

Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

In a previous study from our group, a novel compound, namely CW­33 (ethyl 2­(3',5'­dimethylanilino)­â€‹4­oxo­4,5­dihydrofuran­3­carboxylate) was identified that exhibited antiviral activity for Japanese encephalitis virus (JEV). The viral NS2B­NS3 serine protease serves an important role in cytoplasmic cleavage events that occur during viral polyprotein maturation. The inhibition of viral RNA and protein syntheses was responsible for the antiviral activities of the novel furanonaphthoquinone derivatives that were discovered for the prevention of JEV infection. Consequently, the present study examined the molecular docking simulation of JEV protease with compound CW­33 and its analogues, and developed quantitative structure­activity relationship (QSAR) models to assess the potential antiviral activities of these compounds with regard to JEV. Molecular docking simulation indicated the potential ligand­protein interactions associated with the antiviral activities of these compounds. According to the results of the QSAR models, the secondary amine group was an important moiety required for compound bioactivity, which enabled the formation of hydrogen bonding with the residue Glu155. Furthermore, the aromatic ring mapping of the phenyl moiety of each compound was predicted to form a π­cation interaction with residue Arg76, whereas the hydrophobic feature represented by the ethyl moiety exhibited hydrophobic contacts with residue Glu74. Finally, the hydrophobic substituents in the meta­position of the phenyl ring further contributed to the efficacy of the antiviral activity. These results unravel the structural characteristics that are required for binding of CW­33 to the JEV protease and can be used for potential therapeutic and drug development purposes for JEV.

Asunto(s)

Compuestos de Anilina/farmacología , Antivirales/farmacología , Virus de la Encefalitis Japonesa (Especie)/efectos de los fármacos , Furanos/farmacología , Proteínas no Estructurales Virales/metabolismo , Compuestos de Anilina/química , Antivirales/química , Sitios de Unión , Furanos/química , Concentración 50 Inhibidora , Modelos Lineales , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Máquina de Vectores de Soporte

RESUMEN

A series of emodin analogues have been demonstrated to exhibit potent antiproliferative activity in three human epidermal growth factor receptor 2 (HER2)­overexpressing cell lines. However, in docking simulations, not all of these emodin analogues docked into the HER2 protein binding site. As the epidermal growth factor receptor (EFGR) and HER2 proteins are members of the ErbB family, the present study aimed to determine whether these anthraquinone derivatives exhibit potent antitumour bioactivity due to their inhibition of EGFR protein. Two 2D quantitative structure­activity relationship (QSAR) models, applied using multiple linear regression and a support vector machine, indicated seven representative molecular descriptors of anthraquinone derivatives associated with their antitumour activities. Molecular docking simulation indicated the possible docking poses of binding in the EGFR kinase domain. Two 3D­QSAR models performed by comparative force field analysis and comparative similarity indices analysis indicated the favoured and disfavoured fields for four physicochemical parameters (steric and hydrophobic properties, and hydrogen bond donor and acceptor), which may further improve the antitumour properties. These results demonstrate the benefits of further investigations on the development of lead compounds with improved anticancer bioactivity.

Asunto(s)

Emodina/farmacología , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Emodina/análogos & derivados , Emodina/química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Mutación , Neoplasias/genética , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad Cuantitativa

RESUMEN

Japanese encephalitis virus (JEV) is a member of neurotropic flaviviruses transmitted by mosquito bites, causing severe central nervous system disorders. Current JEV genotype III vaccines have a low protection against genotype I isolates in the risk zone. The lead compound CW-33, ethyl 2-(3',5'-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate, demonstrates the antiviral activity against JEV with an IC50 values of 38.5 µM for virus yield reduction (Int J Mol Sci 2016,17: E1386). This study synthesized fourteen CW-33 analogues containing a fluoro atom or one methoxy group at the C-2, C-3, or C-4 of anilino ring, and then evaluated for their antiviral activity and mechanism. Among 6 amalogues, CW-33A (ethyl 2-(2-fluoroanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate), and CW-33D (ethyl 2-(3-methoxyanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate exhibited antiviral potentials in viral cytopathic effect (CPE) inhibition. CW-33A significantly suppressed the viral protein expression, genome synthesis and intracellular JEV particle production, showing a higher inhibitory effect on JEV yield than CW-33 and CW-33D. The study demonstrated that a mono-fluoro substitution on at the C-2 anilino ring of CW-33 improved the antiviral activity JEV, revealing the structure-activity relationship for developing novel agents against JEV infection.

Asunto(s)

Compuestos de Anilina/farmacología , Antivirales/farmacología , Efecto Citopatogénico Viral/efectos de los fármacos , Encefalitis Japonesa/tratamiento farmacológico , Furanos/farmacología , Meduloblastoma/tratamiento farmacológico , Proteínas Virales/genética , Replicación Viral/efectos de los fármacos , Compuestos de Anilina/química , Antivirales/química , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/virología , Virus de la Encefalitis Japonesa (Especie)/efectos de los fármacos , Encefalitis Japonesa/complicaciones , Encefalitis Japonesa/virología , Furanos/química , Genoma Viral , Genotipo , Humanos , Meduloblastoma/virología , Estructura Molecular

RESUMEN

OBJECTIVES: To evaluate the effect of functional movement screen (FMS)-based functional exercise in patients after anterior cruciate ligament reconstruction (ACLR). DESIGN: Randomized, controlled, single-blind trial. SETTING: Institutional, single center. PATIENTS: A total of 38 patients who underwent ACLR were recruited and randomly assigned to group 1 (n = 19) or group 2 (n = 19). INTERVENTIONS: Both groups received 6-month routine rehabilitation immediately after surgery. From the postoperative fourth to sixth month, group 1 received FMS-based functional exercise plus routine rehabilitation and group 2 received routine rehabilitation only. The FMS-based functional exercise was individualized and customized functional corrective exercise, which was designed based on the 3-month postoperative FMS results. The frequency of rehabilitation was 1 hour per session, twice a week, for a total duration of 6 months. MAIN OUTCOME MEASURES: At 3 and 6 months postoperatively, patients were evaluated by FMS scoring, Lysholm Knee Score, and International Knee Documentation Committee 2000 Score. RESULTS: After the intervention, both groups had significantly increased FMS, Lysholm Knee Score, and International Knee Documentation Committee 2000 score. Group 1 had significantly greater changes in FMS (median: 4 vs 3, P < .001), Lysholm Knee Score (median: 24 vs 16, P = .001), and International Knee Documentation Committee 2000 Score (median: 22 vs 8, P < .001) than group 2. CONCLUSION: The application of FMS-based functional exercise to patients after ACLR resulted in significant improvement in knee function and movements. The authors suggested integrating FMS evaluation and FMS-based training into routine post-ACLR rehabilitation programs.

Asunto(s)

Reconstrucción del Ligamento Cruzado Anterior/rehabilitación , Terapia por Ejercicio , Traumatismos de la Rodilla/rehabilitación , Adulto , Femenino , Humanos , Articulación de la Rodilla/fisiopatología , Masculino , Movimiento , Método Simple Ciego , Adulto Joven

RESUMEN

Photodynamic therapy (PDT) typically involves oxygen (O2 ) consumption and therefore suffers from greatly limited anticancer therapeutic efficacy in tumor hypoxia. Here, it is reported for the first time that amine-terminated, PAMAM dendrimer-encapsulated gold nanoclusters (AuNCs-NH2 ) can produce O2 for PDT via their intrinsic catalase-like activity. The AuNCs-NH2 not only show optimum H2 O2 consumption via the catalase-like activity over the physiological pH range (i.e., pH 4.8-7.4), but also extend such activity to acidic conditions. The possible mechanism is deduced from that the enriched tertiary amines of dendrimers are easily protonated in acidic solutions to facilitate the preadsorption of OH on the metal surface, thereby favorably triggering the catalase-like reaction. By taking advantage of the exciting feature on AuNCs-NH2 , the possibility to supply O2 via the catalase-like activity of AuNCs-NH2 for PDT against hypoxia of cancer cells was further studied. This proof-of-concept study provides a simple way to combine current O2 -dependent cancer therapy of PDT to overcome cancer cell hypoxia, thus achieving more effective anticancer treatments.

Asunto(s)

Catalasa/metabolismo , Oro/química , Oxígeno/química , Fotoquimioterapia/métodos , Catalasa/química , Línea Celular Tumoral , Humanos

RESUMEN

Coronary artery disease (CAD) is the most common cause of heart attack and the leading cause of mortality in the world. It is associated with mitochondrial dysfunction and increased level of reactive oxygen species production. According to the Ottawa Heart Genomics Study genome-wide association study, a recent research identified that Q688 spastic paraplegia 7 (SPG7) variant is associated with CAD as it bypasses the regulation of tyrosine phosphorylation of AFG3L2 and enhances the processing and maturation of SPG7 protein. This study aims to identify potential compounds isolated from Traditional Chinese Medicines (TCMs) as potential lead compounds for paraplegin (SPG7) inhibitors. For the crystallographic structure of paraplegin, the disordered disposition of key amino acids in the binding site was predicted using the PONDR-Fit protocol before virtual screening. The TCM compounds saussureamine C and 3-(2-carboxyphenyl)-4(3H)-quinazolinone, have potential binding affinities with stable H-bonds and hydrophobic contacts with key residues of paraplegin. A molecular dynamics simulation was performed to validate the stability of the interactions between each candidate and paraplegin under dynamic conditions. Hence, we propose these compounds as potential candidates as lead drug from the compounds isolated from TCM for further study in drug development process with paraplegin protein for coronary artery disease.

Asunto(s)

Asparagina/análogos & derivados , Enfermedad de la Arteria Coronaria/genética , Medicamentos Herbarios Chinos/química , Inhibidores Enzimáticos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Quinazolinonas/farmacología , ATPasas Asociadas con Actividades Celulares Diversas , Asparagina/química , Asparagina/farmacología , Sitios de Unión , Simulación por Computador , Enfermedad de la Arteria Coronaria/enzimología , Cristalografía por Rayos X , Medicamentos Herbarios Chinos/farmacología , Inhibidores Enzimáticos/química , Humanos , Metaloendopeptidasas/química , Metaloendopeptidasas/genética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Mutación , Quinazolinonas/química , Relación Estructura-Actividad

RESUMEN

Estrogen-like endocrine disrupting compounds (EEDC) such as bisphenol A, nonylphenol, and phthalic acid esters are toxic compounds that may occur in both raw- and drinking water. The aim of this study was to combine chemical- and bioassay to evaluate the risk of EEDCs in the drinking water treatment plants (DWTPs). Fifty-six samples were collected from seven DWTPs located in northern-, central-, and southern Taiwan from 2011 to 2012 and subjected to chemical analyses and two bioassay methods for total estrogenic activity (E-Screen and T47D-KBluc assay). Among of the considered EEDCs, only dibutyl phthalate (DBP) and di (2-ethylhexyl) phthalate (DEHP) were detected in both drinking and raw water samples. DBP levels in drinking water ranged from

Asunto(s)

Agua Potable/química , Exposición a Riesgos Ambientales/estadística & datos numéricos , Estrógenos/análisis , Aguas Residuales/química , Contaminantes Químicos del Agua/análisis , Purificación del Agua , Compuestos de Bencidrilo/análisis , Bioensayo , Dibutil Ftalato/análisis , Disruptores Endocrinos/análisis , Estradiol/análisis , Femenino , Humanos , Masculino , Fenoles/análisis , Ácidos Ftálicos/análisis , Taiwán

RESUMEN

The effects of synthetic goethite (α-FeOOH) used as the catalyst in catalytic ozonation for the degradation of disinfection by-product (DBP) precursors are investigated. A biofiltration column applied following the catalytic ozonation process is used to evaluate the efficiency of removing DBP precursors via biotreatment. Ozone can rapidly react with aromatic compounds and oxidize organic compounds, resulting in a decrease in the fluorescence intensity of dissolved organic matter (DOM). In addition, catalytic ozonation can break down large organic molecules, which causes a blue shift in the emission-excitation matrix spectra. Water treated with catalytic ozonation is composed of low-molecular structures, including soluble microbial products (SMPs) and other aromatic proteins (APs). The DOM in SMPs and APs is removed by subsequent biofiltration. Catalytic ozonation has a higher removal efficiency for dissolved organic carbon and higher ultraviolet absorbance at 254 nm compared to those of ozonation without a catalyst. The use of catalytic ozonation and subsequent biofiltration leads to a lower DBP formation potential during chlorination compared to that obtained using ozonation and catalytic ozonation alone. Regarding DBP species during chlorination, the bromine incorporation factor (BIF) of trihalomethanes and haloacetic acids increases with increasing catalyst dosage in catalytic ozonation. Moreover, the highest BIF is obtained for catalytic ozonation and subsequent biofiltration.

Asunto(s)

Desinfectantes/química , Filtración , Compuestos de Hierro/química , Minerales/química , Ozono/química , Eliminación de Residuos Líquidos , Contaminantes Químicos del Agua/química , Catálisis

RESUMEN

Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Medicina Tradicional China , Neoplasias/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Receptores Acoplados a Proteínas G/química , Sitios de Unión , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/metabolismo , Neoplasias/patología , Obesidad/patología , Ftalazinas/química , Conformación Proteica , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptor Smoothened , Taiwán

RESUMEN

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted from Lycium chinense Mill. and Abrus precatorius L., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

Asunto(s)

Proteínas Portadoras/química , Química Farmacéutica/métodos , Proteínas de la Membrana/química , Neoplasias/tratamiento farmacológico , Hormonas Tiroideas/química , Asparagina/análogos & derivados , Asparagina/química , Sitios de Unión , Biología Computacional , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Ligandos , Lisina/química , Medicina Tradicional China , Mitosis , Simulación de Dinámica Molecular , Conformación Proteica , Triptófano/análogos & derivados , Triptófano/química , Proteínas de Unión a Hormona Tiroide

RESUMEN

It has been indicated that tumor necrosis factor receptor-associated factor-6 (TRAF6) will upregulate the expression of hypoxia-inducible factor-1α (HIF-1α) and promote tumor angiogenesis. TRAF6 proteins can be treated as drug target proteins for a differentiation therapy against cancers. As structural disordered disposition in the protein may induce the side-effect and reduce the occupancy for ligand to bind with target protein, PONDR-Fit protocol was performed to predict the disordered disposition in TRAF6 protein before virtual screening. TCM compounds from the TCM Database@Taiwan were employed for virtual screening to identify potent compounds as lead compounds of TRAF6 inhibitor. After virtual screening, the MD simulation was performed to validate the stability of interactions between TRAF6 proteins and each ligand. The top TCM compounds, tryptophan, diiodotyrosine, and saussureamine C, extracted from Saussurea lappa Clarke, Bos taurus domesticus Gmelin, and Lycium chinense Mill., have higher binding affinities with target protein in docking simulation. However, the docking pose of TRAF6 protein with tryptophan is not stable under dynamic condition. For the other two TCM candidates, diiodotyrosine and saussureamine C maintain the similar docking poses under dynamic conditions. Hence, we propose the TCM compounds, diiodotyrosine and saussureamine C, as potential candidates as lead compounds for further study in drug development process with the TRAF6 protein against cancer.

Asunto(s)

Medicina Tradicional China/métodos , Neoplasias/tratamiento farmacológico , Factor 6 Asociado a Receptor de TNF/antagonistas & inhibidores , Animales , Asparagina/análogos & derivados , Asparagina/química , Bovinos , Cristalografía por Rayos X , Diyodotirosina/química , Humanos , Enlace de Hidrógeno , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ligandos , Simulación de Dinámica Molecular , Neoplasias/patología , Neovascularización Patológica , Unión Proteica , Estructura Secundaria de Proteína , Triptófano/química

RESUMEN

Rheumatoid arthritis (RA) is a chronic inflammatory disease that will affect quality of life and, working efficiency, and produce negative thoughts for patients. Current therapy of RA is treated with disease-modifying antirheumatic drugs (DMARDs). Although most of these treatment methods are effective, most patients still have a pleasant experience either due to poor efficacy or side effects or both. Interleukin-6 receptor (IL6R) is important in the pathogenesis of RA. In this study, we would like to detect the potential candidates which inhibit IL6R against RA from traditional Chinese medicine (TCM). We use TCM compounds from the TCM Database@Taiwan for virtually screening the potential IL6R inhibitors. The TCM candidate compound, calycosin, has potent binding affinity with IL6R protein. The molecular dynamics simulation was employed to validate the stability of interaction in the protein complex with calycosin. The analysis indicates that protein complex with calycosin is more stable. In addition, calycosin is known to be one of the components of Angelica sinensis, which has been indicated to have an important role in the treatment of rheumatoid arthritis. Therefore, calycosin is a potential candidate as lead compounds for further study in drug development process with IL6R protein against rheumatoid arthritis.

Asunto(s)

Antirreumáticos/química , Artritis Reumatoide/tratamiento farmacológico , Isoflavonas/química , Medicina Tradicional China , Receptores de Interleucina-6/antagonistas & inhibidores , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptores de Interleucina-6/química , Receptores de Interleucina-6/metabolismo

RESUMEN

A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.

Asunto(s)

Isocitrato Deshidrogenasa/química , Medicina Tradicional China , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Sulfonamidas/administración & dosificación , Dominio Catalítico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Mitocondrias/enzimología , Simulación del Acoplamiento Molecular , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Neoplasias/patología , Compuestos de Fenilurea/química , Mutación Puntual , Sulfonamidas/química

RESUMEN

Recently, cardiovascular disease, also known as loop circulatory system diseases or disorders, is one of the serious diseases including heart disease, stroke, atherosclerosis, myocardial infarction, hypertension, hypotension, and thrombosis. Human pregnane X receptor, PXR, plays a crucial role in exogenous and endobiotic metabolism for rabbit, rat, mouse, and human. The PXR activation can protect the blood vessels from damage of hazardous substances. In this study we aim to investigate the potent lead compounds as PXR receptor agonist against cardiovascular disease. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as PXR agonists from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, bis(4-hydroxybenzyl) ether mono-ß-D-glucopyranoside (BEMG), ixerisoside, and tangshenoside II, have displayed higher potent binding affinities than the positive control, PNU-142721, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and PXR protein under dynamic conditions, top TCM compounds, BEMG and tangshenoside II, maintain most of interactions with PXR protein, which keep the ligand binding stable in the binding domain. Hence, we propose BEMG and tangshenoside II as potential lead compounds for further study in drug development process with the PXR protein.

Asunto(s)

Enfermedades Cardiovasculares/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Receptores de Esteroides/antagonistas & inhibidores , Animales , Teorema de Bayes , Medicamentos Herbarios Chinos/química , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/metabolismo , Ligandos , Modelos Lineales , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptor X de Pregnano , Estructura Secundaria de Proteína , Receptores de Esteroides/química , Máquina de Vectores de Soporte , Termodinámica

RESUMEN

A recent research demonstrates that the inhibition of mammalian target of rapamycin (mTOR) improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 and π interactions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted from Picrasma quassioides (D. Don) Benn. and Vitex negundo L. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.

Asunto(s)

Enfermedad de Leigh/tratamiento farmacológico , Medicina Tradicional China , Relación Estructura-Actividad Cuantitativa , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Sitios de Unión , Simulación por Computador , Bases de Datos Factuales , Descubrimiento de Drogas , Humanos , Enfermedad de Leigh/patología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Serina-Treonina Quinasas TOR/química , Taiwán