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1.
PLoS Comput Biol ; 7(12): e1002315, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22215997

RESUMEN

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.


Asunto(s)
Antivirales/farmacología , Medicamentos Herbarios Chinos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Antivirales/química , Aporfinas/química , Aporfinas/farmacología , Inteligencia Artificial , Bases de Datos Factuales , Diterpenos/química , Diterpenos/farmacología , Farmacorresistencia Viral , Medicamentos Herbarios Chinos/química , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Gripe Humana/virología , Medicina Tradicional China , Simulación de Dinámica Molecular , Mutación , Máquina de Vectores de Soporte
2.
PLoS Comput Biol ; 7(10): e1002189, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22022246

RESUMEN

Overexpression of epidermal growth factor receptor (EGFR) has been associated with cancer. Targeted inhibition of the EGFR pathway has been shown to limit proliferation of cancerous cells. Hence, we employed Traditional Chinese Medicine Database (TCM Database@Taiwan) (http://tcm.cmu.edu.tw) to identify potential EGFR inhibitor. Multiple Linear Regression (MLR), Support Vector Machine (SVM), Comparative Molecular Field Analysis (CoMFA), and Comparative Molecular Similarities Indices Analysis (CoMSIA) models were generated using a training set of EGFR ligands of known inhibitory activities. The top four TCM candidates based on DockScore were 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid, and all had higher binding affinities than the control Iressa®. The TCM candidates had interactions with Asp855, Lys716, and Lys728, all which are residues of the protein kinase binding site. Validated MLR (r²â€Š= 0.7858) and SVM (r²â€Š= 0.8754) models predicted good bioactivity for the TCM candidates. In addition, the TCM candidates contoured well to the 3D-Quantitative Structure-Activity Relationship (3D-QSAR) map derived from the CoMFA (q²â€Š= 0.721, r²â€Š= 0.986) and CoMSIA (q²â€Š= 0.662, r²â€Š= 0.988) models. The steric field, hydrophobic field, and H-bond of the 3D-QSAR map were well matched by each TCM candidate. Molecular docking indicated that all TCM candidates formed H-bonds within the EGFR protein kinase domain. Based on the different structures, H-bonds were formed at either Asp855 or Lys716/Lys728. The compounds remained stable throughout molecular dynamics (MD) simulation. Based on the results of this study, 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid are suggested to be potential EGFR inhibitors.


Asunto(s)
Bases de Datos Factuales , Receptores ErbB/antagonistas & inhibidores , Algoritmos , Receptores ErbB/química , Receptores ErbB/metabolismo , Enlace de Hidrógeno , Ligandos , Modelos Moleculares , Simulación de Dinámica Molecular , Conformación Proteica , Relación Estructura-Actividad Cuantitativa , Taiwán
3.
Int J Food Microbiol ; 108(3): 364-8, 2006 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-16466821

RESUMEN

Alicyclobacillus acidoterrestris is a thermophilic spore-forming bacterium that spoils acidic juices. In the orchard, apples may be contaminated with spores which can potentially grow in the resulting juice and cause spoilage. This study was undertaken to evaluate the efficacy of gaseous chlorine dioxide against A. acidoterrestris spores on apple surfaces. A. acidoterrestris spores were inoculated onto apple surfaces and were placed at room temperature, in a tightly sealed chamber containing a chlorine dioxide generating sachet, low, medium, or high release, for 30 min, 1, 2, and 3 h. After exposure, surviving spores were enumerated on K agar. Chlorine dioxide treated apples were stored at 4 degrees C for 7 days to assess the effect on visual quality. Inoculated, untreated apples served as the visual quality control. After exposure to high and medium release sachets for 1 h, spores were reduced to an undetectable level, a 5 log10 reduction; however, visual quality was compromised. After 1, 2, and 3 h of exposure to low release sachets, spore reductions were 2.7, 3.7, and 4.5 log10, respectively. And, after 7 days of storage, there were no significant visual quality differences between the apples exposed to low release sachet for all treatment times when compared to the control. Gaseous chlorine dioxide can effectively reduce viable A. acidoterrestris spores on apple surfaces. Due to the efficacy and easy of use, chlorine dioxide gas sachets may be useful to maintain apple quality during storage and shipping.


Asunto(s)
Antibacterianos/farmacología , Compuestos de Cloro/farmacología , Conservación de Alimentos/métodos , Bacilos Grampositivos Formadores de Endosporas/efectos de los fármacos , Malus/microbiología , Óxidos/farmacología , Esporas Bacterianas/crecimiento & desarrollo , Recuento de Colonia Microbiana , Seguridad de Productos para el Consumidor , Microbiología de Alimentos , Bacilos Grampositivos Formadores de Endosporas/crecimiento & desarrollo , Bacilos Grampositivos Formadores de Endosporas/fisiología , Humanos , Factores de Tiempo
4.
Int J Food Microbiol ; 105(3): 369-76, 2005 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-16126293

RESUMEN

Alicyclobacillus spp. are thermoacidophilic, spore-forming bacteria. Some of which cause spoilage in pasteurized and heat-treated apple juice products through the production of guaiacol. Fourier transform infrared (FT-IR) spectroscopy was used to discriminate between eight Alicyclobacillus strains (WAC, 81-2, Oly#21, 51-1, KF, 1016, 1101, and A-Gala A4) in apple juice. FT-IR vibrational combination bands reflected compositional differences in the cell membranes of Alicyclobacillus strains in the "fingerprint region" at wavenumbers between 1500 and 800 cm(-1). Distinctive segregation among spectral sample clusters of different Alicyclobacillus strains was observed using principal component analysis (PCA). Two closely related strains (1016 and 1101) of Alicyclobacillus acidoterrestris could be distinguished, suggesting that this method can be highly selective. Results of soft independent modeling of class analogy (SIMCA) demonstrated that guaiacol-producing and non-guaiacol producing Alicyclobacillus strains could be differentiated up to 89% of the time. This technique may provide a tool for fruit juice producers to detect Alicyclobacillus rapidly and to monitor and control guaiacol formation.


Asunto(s)
Bebidas/microbiología , Contaminación de Alimentos/análisis , Bacilos Grampositivos Formadores de Endosporas/clasificación , Bacilos Grampositivos Formadores de Endosporas/aislamiento & purificación , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Malus , Análisis Multivariante , Filogenia , Análisis de Componente Principal , Sensibilidad y Especificidad , Especificidad de la Especie
5.
J Food Prot ; 66(11): 2146-50, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14627297

RESUMEN

A new rapid method for monitoring coliforms was developed on the basis of the instant gelling effects of alginate and calcium. The effectiveness of this new method in the detection of coliforms was evaluated. Tests involving Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, total coliforms in milk, cold-injured coliforms, and total coliforms in raw milk were carried out. The bacterial samples were diluted in 0.2% peptone water containing 90 mM CaCl2 and added into test tubes containing modified purple broth base medium. Coliform concentrations were determined on the basis of the time of color change and gas production in the alginate tubes. All results obtained by the alginate method correlated strongly with those obtained by the conventional violet red bile agar (VRBA) plating method. The alginate method reduced detection time by 12 to 14 h compared with the conventional VRBA plating method. The alginate method can be applied in field studies more easily than melted-agar systems can. The results of this study indicate that the alginate method is an accurate, rapid, simple, and economical way to monitor and estimate concentrations of total coliforms in food.


Asunto(s)
Alginatos , Recuento de Colonia Microbiana/métodos , Enterobacteriaceae/aislamiento & purificación , Ácido Glucurónico , Ácidos Hexurónicos , Leche/microbiología , Animales , Técnicas Bacteriológicas , Calcio/metabolismo , Enterobacteriaceae/metabolismo , Fermentación , Microbiología de Alimentos , Geles , Reproducibilidad de los Resultados , Factores de Tiempo
6.
J Biomol Struct Dyn ; 32(5): 776-91, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-23730798

RESUMEN

Insomnia is a prominent modern disease that affects an increasing population. Undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Virtual screening of traditional chinese medicine Database@Taiwan (TCM Database@Taiwan) identified 2-O-Caffeoyl tartaric acid (1), 2-O-Feruloyl tartaric acid (2), and Mumefural (3) as potential agonists for both gamma-amino butyric acid (GABA) or benzodiazepine (BZ) binding sites. The TCM candidates exhibited higher affinity than GABA and Zolpidem, a phenomenon that could be attributed to higher quantity of stabilizing H-bonds. Efficacy profiles using support vector machines and pharmacophore contour also suggest drug potential of the TCM candidates. Fragments added to the de novo derivatives 3a, 3b, 3c for GABA binding site, and 1a, 2a, and 3d for BZ binding site contributed to new binding sites and structural stability, further optimizing binding to GABA or BZ binding sites. Increased opening of the ion channel by candidate ligands provide strong support for their potential biological functions. The dual binding properties of the TCM candidates present a unique opportunity to develop twin-targeting drugs with less side effects. Derivative structures can be used as starting points for developing high affinity GABAA receptor agonists with specificity towards GABA binding site and BZ binding site.


Asunto(s)
Ácidos Cafeicos/química , Ácido Cítrico/análogos & derivados , Ácidos Cumáricos/química , Medicamentos Herbarios Chinos/química , Furanos/química , Agonistas del GABA/química , Receptores de GABA-A/química , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Tartratos/química , Sitios de Unión , Ácido Cítrico/química , Bases de Datos de Compuestos Químicos , Humanos , Medicina Tradicional China , Simulación de Dinámica Molecular , Ácido gamma-Aminobutírico/química
7.
J Biomol Struct Dyn ; 32(5): 683-93, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-23600691

RESUMEN

N-methyl D-aspartate receptors (NMDARs), a subclass of glutamate receptors have broad actions in neural transmission for major brain functions. Overactivation of NMDARs leading to "excitotoxicity" is the underlying mechanism of neuronal death in a number of neurological diseases, especially stroke. Much research effort has been directed toward developing pharmacological agents to modulate NMDAR actions for treating neurological diseases, in particular stroke. Here, we report that Alliin, a sulfoxide in fresh garlic, exhibits affinity toward NR2A as well as NR2B receptors based on virtual screening. Biological activities of Alliin on these two receptors were confirmed in electrophysiological studies. Ligand-binding site closure, a structural change precluding ion channel opening, was observed with Alliin during 100 ns molecular dynamics simulation. Alliin interactions with NR2A and NR2B suggest that residues E/A413, H485, T690, and Y730 may play important roles in the conformation shift. Activation of NR2A and NR2B by Alliin can be differentiated from that caused by glutamate, the endogenous neurotransmitter. These characteristic molecular features in NR2A and NR2B activation provide insight into structural requirements for future development of novel drugs with selective interaction with NR2A and NR2B for treating neurological diseases, particularly stroke.


Asunto(s)
Cisteína/análogos & derivados , Receptores de N-Metil-D-Aspartato/agonistas , Cisteína/química , Cisteína/farmacología , Bases de Datos de Compuestos Químicos , Células HEK293 , Humanos , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Técnicas de Placa-Clamp , Conformación Proteica , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo
8.
J Biomol Struct Dyn ; 31(11): 1219-35, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23146021

RESUMEN

Insulin-degrading enzyme (IDE) gene is one of the type 2 diabetes mellitus susceptibility genes specific to the Han Chinese population. IDE, a zinc-metalloendopeptidase, is a potential target for controlling insulin degradation. Potential lead compounds for IDE inhibition were identified from traditional Chinese medicine (TCM) through virtual screening and evaluation of their pharmacokinetic properties of absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics (MD) simulation was performed to validate the stability of complexes from docking simulation. The top three TCM compounds, dihydrocaffeic acid, isopraeroside IV, and scopolin, formed stable H-bond interactions with key residue Asn139, and were linked to active pocket residues His108, His112, and Glu189 through zinc. Torsion angle trajectories also indicated some stable interactions for each ligand with IDE. Molecular level analysis revealed that the TCM candidates might affect IDE through competitive binding to the active site and steric hindrance. Structural feature analysis reveals that high amounts of hydroxyl groups and carboxylic moieties contribute to anchor the ligand within the complex. Hence, we suggest the top three TCM compounds as potential inhibitor leads against IDE protein to control insulin degradation for type 2 diabetes mellitus. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:29.


Asunto(s)
Pueblo Asiatico , Ácidos Cafeicos/química , Cumarinas/química , Diabetes Mellitus Tipo 2/enzimología , Glucósidos/química , Hipoglucemiantes/química , Insulisina/antagonistas & inhibidores , Sitios de Unión , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/genética , Humanos , Enlace de Hidrógeno , Insulisina/química , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad
9.
Sci Rep ; 3: 844, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23378894

RESUMEN

FAAH-like anandamide transporter (FLAT) regulates anandamide transport for hydrolysis and may be an attractive drug target for pain regulation. We aimed to discover potential FLAT antagonists from traditional Chinese medicine (TCM) using virtual screening, ligand-based drug design and molecular dynamics simulation (MD). Guineensine and Retrofractamide A exhibited high Dock Scores in FLAT. Consensus from multiple linear regression (MLR; R(2) = 08973) and support vector machine (SVM; R(2) = 0.7988) showed similar bioactivities for Guineensine and the FAAH-1 inhibitor (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Contour of Guineensine to CoMFA and CoMSIA features also imply bioactivity. MD revealed shake or vibration in the secondary structure of FLAT complexed with Guineensine and (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Ligand movement might contribute to protein changes leading to vibration patterns. Violent vibrations leading to an overall decrease in FLAT function could be the underlying mechanism for Guineensine. Here we suggest Guineensine as a drug-like compound with potential application in relieving neuropathic pain by inhibiting FLAT.


Asunto(s)
Alquenos/química , Amidas/química , Benzodioxoles/química , Diseño de Fármacos , Compuestos Heterocíclicos con 2 Anillos/química , Alquenos/uso terapéutico , Amidas/uso terapéutico , Secuencia de Aminoácidos , Animales , Benzodioxoles/uso terapéutico , Sitios de Unión , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/metabolismo , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Humanos , Modelos Lineales , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Neuralgia/tratamiento farmacológico , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Ratas , Alineación de Secuencia , Máquina de Vectores de Soporte
10.
J Biomol Struct Dyn ; 31(12): 1358-69, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23140436

RESUMEN

Overexpression of epidermal growth factor receptor (EGFR), Her2, and uroporphyrinogen decarboxylase (UROD) occurs in a variety of malignant tumor tissues. UROD has potential to modulate tumor response of radiotherapy for head and neck cancer, and EGFR and Her2 are common drug targets for the treatment of head and neck cancer. This study attempts to find a possible lead compound backbone from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) for EGFR, Her2, and UROD proteins against head and neck cancer using computational techniques. Possible traditional Chinese medicine (TCM) lead compounds had potential binding affinities with EGFR, Her2, and UROD proteins. The candidates formed stable interactions with residues Arg803, Thr854 in EGFR, residues Thr862, Asp863 in Her2 protein, and residues Arg37, Arg41 in UROD protein, which are key residues in the binding or catalytic domain of EGFR, Her2, and UROD proteins. Thus, the TCM candidates indicated a possible molecule backbone for evolving potential inhibitors for three drug target proteins against head and neck cancer.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/prevención & control , Receptor ErbB-2/antagonistas & inhibidores , Uroporfirinógeno Descarboxilasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Simulación por Computador , Bases de Datos Factuales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Receptores ErbB/química , Receptores ErbB/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Medicina Tradicional China/métodos , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Estructura Terciaria de Proteína , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo , Taiwán , Uroporfirinógeno Descarboxilasa/química , Uroporfirinógeno Descarboxilasa/metabolismo
11.
J Biomol Struct Dyn ; 31(12): 1411-39, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23249175

RESUMEN

Cognitive repair by insulin-like growth factor-I (IGF-I) through activation of insulin-like growth factor-I receptor (IGF-IR) is well established, but not used for clinical therapy due to its link to cancer. We hypothesize that IGF-IR activation rather than IGF-I per se may be essential for cognitive repair and attempted to identify ligands from traditional Chinese medicine (TCM) with drug-like potential towards IGF-IR. TCM ligands, 3-(2-carboxyphenyl)-4(3H)-quinazolinone from Isatisin digotica, (+)-N-methyllaurotetanine from Lindera aggregate, and (+)-1(R)-Coclaurine from Nelumbonucifera Gaertn, exhibited high binding affinities and good blood brain barrier (BBB) penetration crucial for accessing IGF-IR. Stable complex formation of the candidates was observed during molecular dynamics (MD) simulation. Interactions with Leu975 and Gly1055 or Asp1056 were important for ligand binding. Amino acid distance analysis revealed residues 974/975, 984-986, 996-1006, 1040-1056, and 1122-1135 as "hotspots" for ligand binding in IGF-IR. Versatile entry pathways for the TCM candidates suggest high accessibility to the binding site. Blockage of the binding site opening by the TCM candidates limits binding site access by other compounds. Multiple linear regression (R² = 0.9715), support vector machine (R² = 0.9084), Bayesian network (R² =0.8233) comparative molecular field analysis (CoMFA, R² = 0.9941), and comparative molecular similarity indices analysis (CoMSIA, R² = 0.9877) models consistently suggest that the TCM candidates might exert bioactivity on IGF-IR. Contour of representative MD conformations to CoMFA and CoMSIA maps exhibits similar results. Properties including BBB passage, evidence of ability to form stable complexes with IGF-IR by MD simulation, and predicted bioactivity suggest that the TCM candidates have drug-like properties and might have potential as cognitive-enhancing drugs.


Asunto(s)
Cognición/fisiología , Medicina Tradicional China/métodos , Memoria/fisiología , Plantas Medicinales/química , Aporfinas/química , Aporfinas/metabolismo , Aporfinas/farmacología , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Teorema de Bayes , Sitios de Unión , Unión Competitiva , Cognición/efectos de los fármacos , Glicina/química , Glicina/metabolismo , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Isoquinolinas/farmacología , Leucina/química , Leucina/metabolismo , Ligandos , Memoria/efectos de los fármacos , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/metabolismo
12.
PLoS One ; 7(9): e43932, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22970152

RESUMEN

Pancreatic triacylglycerol lipase (PNLIP) are primary lipases that are critical for triacylglyceride digestion in human. Since reduced metabolism of triacylglyceride might be a plausible concept for weight loss, we screened for potential PNLIP inhibitors from traditional Chinese medicine (TCM) with the aim to identify weight loss candidate compounds. TCM candidates Aurantiamide, Cnidiadin, and 2-hexadecenoic acid exhibited higher Dock Scores than the commercial drug Orlistat, and were also predicted to have inhibitory characteristics against PNLIP using constructed MLR (R(2) = 0.8664) and SVM (R(2) = 0.9030) models. Molecular dynamics indicated that the TCM-PNLIP complexes formed were stable. We identified that the PNLIP binding site has several residues that can serve as anchors, and a hydrophobic corridor that provides additional stability to the complex. Aurantiamide, Cnidiadin, and 2-hexadecenoic acid all have features that correspond to these binding site features, indicating their potential as candidates for PNLIP inhibitors. The information presented in this study may provide helpful insights to designing novel weight-control drugs.


Asunto(s)
Biología Computacional/métodos , Inhibidores Enzimáticos/farmacología , Lipasa/antagonistas & inhibidores , Medicina Tradicional China , Páncreas/enzimología , Sitios de Unión , Inhibidores Enzimáticos/análisis , Inhibidores Enzimáticos/química , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ligandos , Modelos Lineales , Lipasa/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Secundaria de Proteína , Máquina de Vectores de Soporte
13.
J Biomol Struct Dyn ; 30(6): 662-83, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22731403

RESUMEN

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.


Asunto(s)
Hipoglucemiantes/química , Simulación del Acoplamiento Molecular , PPAR alfa/química , PPAR delta/química , PPAR gamma/química , Secuencia de Aminoácidos , Secuencia Conservada , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Medicina Tradicional China , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gamma/agonistas , Bibliotecas de Moléculas Pequeñas , Homología Estructural de Proteína
14.
PLoS One ; 7(11): e50087, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23209648

RESUMEN

Uroporphyrinogen decarboxylase (UROD) has been suggested as a protectant against radiation for head and neck cancer (HNC). In this study, we employed traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) to screen for drug-like candidates with potential UROD inhibition characteristics using virtual screening techniques. Isopraeroside IV, scopolin, and nodakenin exhibited the highest Dock Scores, and were predicted to have good Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Two common moieties, 2H-chromen-2-one and glucoside, were observed among the top TCM candidates. Cross comparison of the docking poses indicated that candidates formed stable interactions with key binding and catalytic residues of UROD through these two moieties. The 2H-chromen-2-one moiety enabled pi-cation interactions with Arg37 and H-bonds with Tyr164. The glucoside moiety was involved in forming H-bonds with Arg37 and Asp86. From our computational results, we propose isopraeroside IV, scopolin, and nodakenin as ligands that might exhibit drug-like inhibitory effects on UROD. The glucoside and 2H-chromen-2-one moieties may potentially be used for designing inhibitors of UROD.


Asunto(s)
Medicina Tradicional China/métodos , Uroporfirinógeno Descarboxilasa/metabolismo , Algoritmos , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Glucósidos/metabolismo , Humanos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Ligandos , Modelos Químicos , Simulación de Dinámica Molecular , Unión Proteica , Programas Informáticos , Tirosina/genética , Uroporfirinógeno Descarboxilasa/química
15.
Mol Biosyst ; 7(12): 3366-74, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22012120

RESUMEN

New-type oseltamivir-resistant H1N1 influenza viruses have been a major threat to human health since the 2009 flu pandemic. To resolve the drug resistance issue, we aimed to identify a new type of inhibitors against H1 from traditional Chinese medicine (TCM) by employing the world's largest TCM database () for virtual screening and molecular dynamics (MD). From the virtual screening results, sodium (+)-isolaricireinol-2 alpha-sulfate, sodium 3,4-dihydroxy-5-methoxybenzoic acid methyl ester-4-sulfate, sodium (E)-7-hydroxy-1,7-bis(4-hydroxyphenyl)hept-5-ene-3S-sulfonate, and 3-methoxytyramine-betaxanthin were identified as potential drug-like compounds. MD simulation of the binding poses with the key residues Asp103 and Glu83, as well as other binding site residues, identified higher numbers of hydrogen bonds than N-Acetyl-D-Glucosamine (NAG), the natural ligand of the esterase domain in H1. Ionic bonds, salt bridges, and electrostatic energy also contribute to binding stability. Key binding residues include Lys71, Glu83, Asp103, and Arg238. Structural moieties promoting H-bond or salt bridge formations at these locations greatly contribute to a stable ligand-protein complex. An available sodium atom for ionic interactions with Asp103 can further stabilize the ligands. Based on virtual screening, MD simulation, and interaction energy evaluation, TCM candidates demonstrate good potential as novel H1 inhibitors. In addition, the identified stabilizing features can provide insights for designing highly stable H1 inhibitors.


Asunto(s)
Antivirales/farmacología , Medicamentos Herbarios Chinos/farmacología , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Antivirales/metabolismo , Sitios de Unión , Bases de Datos Factuales , Descubrimiento de Drogas , Farmacorresistencia Viral , Medicamentos Herbarios Chinos/metabolismo , Humanos , Gripe Humana/virología , Medicina Tradicional China/métodos , Modelos Moleculares , Simulación de Dinámica Molecular , Unión Proteica , Taiwán
16.
PLoS One ; 6(12): e28793, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22174899

RESUMEN

The relationship between abnormal HER2 expression and cancer is important in cancer therapeutics. Formation and spread of cancer cells may be restricted by inhibiting HER2. We conducted ligand-based and structure-based studies to assess the potency of natural compounds as potential HER2 inhibitors. Multiple linear regression (MLR) and support vector machine (SVM) models were constructed to predict biological activities of natural compounds, and molecular dynamics (MD) was used to assess their stability with HER2 under a dynamic environment. Predicted bioactivities of the natural compounds ranged from 6.014-9.077 using MLR (r(2) = 0.7954) and 5.122-6.950 using SVM (r(2) = 0.8620). Both models were in agreement and suggest bioactivity based on candidate structure. Conformation changes caused by MD favored the formation of stabilizing H-bonds. All candidates had higher stability than Lapinatib, which may be due to the number and spatial distribution of additional H-bonds and hydrophobic interactions. Amino acids Lys724 and Lys736 are critical for binding in HER2, and Thr798, Cys805, and Asp808 are also important for increased stability. Candidates may block the entrance to the ATP binding site located within the inner regions and prevent downstream activation of HER2. Our multidirectional approach indicates that the natural compounds have good ligand efficacy in addition to stable binding affinities to HER2, and should be potent candidates of HER2 inhibitors. With regard to drug design, designing HER2 inhibitors with carboxyl or carbonyl groups available for H-bond formation with Lys724 and Lys736, and benzene groups for hydrophobic contact with Cys805 may improve protein-ligand stability.


Asunto(s)
Productos Biológicos/análisis , Productos Biológicos/farmacología , Bases de Datos como Asunto , Inhibidores de Proteínas Quinasas/análisis , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Aminoácidos/metabolismo , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Ligandos , Modelos Lineales , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/química , Receptor ErbB-2/metabolismo , Máquina de Vectores de Soporte , Termodinámica
17.
J Biomol Struct Dyn ; 29(3): 471-83, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22066534

RESUMEN

Overweight and obesity are common health problems in modern society, particularly in developed countries. Excessive body mass has been linked to numerous diseases, such as cardiovascular diseases, diabetes, and cancer. Fat mass and obesity-associated protein (FTO) activity have direct impact on food intake and results in obesity. Inhibition of FTO activity may cause weight loss and reduce obese-linked health risks. We investigated the potential weight loss effects of traditional Chinese medicine (TCM), particularly by inhibiting FTO functions. Molecular docking was performed to screen TCM compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw). Three candidates were identified that contained either a tetrahydropyridine group or potent electronegative phenol group in the structure scaffold. Molecular dynamics simulation analysis of the docking poses of each complex indicated stabilizing trends in the protein-ligand complex movements. In addition, the number of hydrogen bonds increased throughout the 20 ns simulation. These results suggest that these TCM candidates could be potential FTO inhibitors through competitive inhibition.


Asunto(s)
Fármacos Antiobesidad/química , Peso Corporal/efectos de los fármacos , Medicina Tradicional China , Proteínas/antagonistas & inhibidores , Pérdida de Peso , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Fármacos Antiobesidad/metabolismo , Sitios de Unión , Bases de Datos Factuales , Humanos , Enlace de Hidrógeno , Obesidad/tratamiento farmacológico , Conformación Proteica , Proteínas/química , Proteínas/metabolismo
18.
Chem Biol Drug Des ; 78(4): 679-88, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21801310

RESUMEN

Microsomal prostaglandin E synthase-1 (mPGES-1) is the key enzyme for prostaglandin E2 (PGE2) generation during inflammation and is a potential target for designing anti-inflammatory drugs. Potential inhibitors of m-PGES-1 were selected from traditional Chinese medicine (TCM Database@Taiwan) based on the pharmacophore map generated by the top HypoGen hypothesis and validated using structure- and ligand-based analysis. Key features for potential m-PGES-1 inhibitors include pi-interactions and H-bond donors. TCM compounds, shanciol B, shanciol A, castilliferol, and aurantiamide acetate, contoured to the quantitative structure-activity relationship pharmacophore and exhibited high docking scores and binding stability with m-PGES-1. Bioactivity models multiple linear regression (MLR) and support vector machine also supported activity predictions for the candidate compounds. Our results indicate that the investigated TCM compounds could be of use for development into mPGES-1 inhibitors.


Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Descubrimiento de Drogas , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Medicina Tradicional China , Microsomas/enzimología , Simulación de Dinámica Molecular , Prostaglandina-E Sintasas , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Máquina de Vectores de Soporte
19.
Int J Food Microbiol ; 144(1): 141-6, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20926150

RESUMEN

Alfalfa and other seed sprouts have been implicated in several Escherichia coli O157:H7 and Salmonella spp. human illness outbreaks in the U.S. Continuing food safety issues with alfalfa seeds necessitate the need for discovery and use of novel and effective antimicrobials. The potential use of caprylic acid (CA) and monocaprylin (MC) for reducing E. coli O157:H7 and Salmonella spp. populations on alfalfa seeds was evaluated. The effectiveness of three concentrations of CA and MC (25, 50, and 75 mM) to reduce E. coli O157:H7 and Salmonella spp. populations in 0.1% peptone water and on alfalfa seeds was evaluated. Surviving populations of E. coli O157:H7 and Salmonella spp. were enumerated by direct plating on tryptic soy agar (TSA). Non-inoculated alfalfa seeds were soaked for up to 120 min to evaluate the effect of CA and MC solutions on seed germination rate. For planktonic cells, the efficacy of the treatments was: 75 MC > 50 MC > 25 MC > 75 CA > 50 CA > 25 CA. Both E. coli O157:H7 and Salmonella spp. were reduced to below the detection limit (0.6 log CFU/ml) within 10 min of exposure to 75 MC from initial populations of 7.65 ± 0.10 log CFU/ml and 7.71 ± 0.11 log CFU/ml, respectively. Maximum reductions of 1.56 ± 0.25 and 2.56 ± 0.17 log CFU/g for E. coli O157:H7 and Salmonella spp., respectively, were achieved on inoculated alfalfa seeds (from initial populations of 4.74 ± 0.62 logCFU/g and 5.27±0.20logCFU/g, respectively) when treated with 75 MC for 90 min. Germination rates of CA or MC treated seeds ranged from 84% to 99%. The germination rates of CA or MC soaked seeds and water soaked seeds (control) were similar (P > 0.05) for soaking times of ≤ 90 min. Monocaprylin (75 mM) can be used to reduce E. coli O157:H7 and Salmonella spp. on alfalfa seeds without compromising seed viability.


Asunto(s)
Antiinfecciosos/farmacología , Caprilatos/farmacología , Escherichia coli O157/efectos de los fármacos , Microbiología de Alimentos/métodos , Glicéridos/farmacología , Medicago sativa/microbiología , Salmonella/efectos de los fármacos , Recuento de Colonia Microbiana , Germinación/efectos de los fármacos , Medicago sativa/efectos de los fármacos , Semillas/efectos de los fármacos , Semillas/microbiología
20.
Int J Food Microbiol ; 141(3): 236-41, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20557966

RESUMEN

This study evaluates the antimicrobial effectiveness of epsilon-polylysine against Escherichia coli O157:H7, Salmonella typhimurium and Listeria monocytogenes in laboratory media and roast beef slurry. epsilon-Polylysine supplemented laboratory media and roast beef slurry were inoculated with three-strain cocktails of each pathogen and survival was periodically monitored using conventional spread plating. Inoculated laboratory media was stored at room temperature (22 degrees C) for 48 h, and inoculated roast beef slurry was stored at 4 degrees C for up to 7 days. Maximum log reductions in laboratory media/roast beef slurry were 6.01+/-1.43/3.81+/-0.37, >7.82+/-0.05/5.23+/-0.08, and 4.58+/-0.86/5.83+/-0.48 for E. coli O157:H7, S. typhimurium, and L. monocytogenes, respectively. Injured cells were produced as a result of exposure to polylysine. This study confirms the effectiveness of polylysine against pathogens in laboratory media, and demonstrates its potential as a novel antimicrobial agent in complex food matrix such as roast beef.


Asunto(s)
Antibacterianos/farmacología , Escherichia coli O157/efectos de los fármacos , Comida Rápida/microbiología , Conservantes de Alimentos/farmacología , Listeria monocytogenes/efectos de los fármacos , Carne/microbiología , Polilisina/farmacología , Salmonella typhimurium/efectos de los fármacos , Animales , Bovinos , Escherichia coli O157/crecimiento & desarrollo , Listeria monocytogenes/crecimiento & desarrollo , Viabilidad Microbiana/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo
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