RESUMO
CtpF is a Ca2+ transporter P-type ATPase key to the response to stress conditions and to Mycobacterium tuberculosis virulence, therefore, an interesting target for the design of novel anti-Mtb compounds. In this work, molecular dynamics simulations of four previously identified CtpF inhibitors allowed recognizing the key protein-ligand (P-L) interactions, which were then used to perform a pharmacophore-based virtual screening (PBVS) of 22 million compounds from ZINCPharmer. The top-rated compounds were then subjected to molecular docking, and their scores were refined by MM-GBSA calculations. In vitro assays showed that ZINC04030361 (Compound 7) was the best promising candidate, showing a MIC of 25.0 µg/mL, inhibition of Ca2+-ATPase activity (IC50) of 3.3 µM, cytotoxic activity of 27.2 %, and hemolysis of red blood cells lower than 0.2 %. Interestingly, the ctpF gene is upregulated in the presence of compound 7, compared to other alkali/alkaline P-type ATPases coding genes, strongly suggesting that CtpF is a compound 7-specific target.
Assuntos
Mycobacterium tuberculosis , Mycobacterium tuberculosis/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Simulação de Dinâmica Molecular , Proteínas de Membrana Transportadoras/metabolismo , Adenosina Trifosfatases/metabolismo , Membrana Celular/metabolismo , Antituberculosos/farmacologia , Antituberculosos/metabolismo , Proteínas de Bactérias/metabolismoRESUMO
Digestive enzymes are currently considered important therapeutic targets for the treatment of obesity and some associated metabolic diseases, such as type 2 diabetes. Piper cumanense is a species characterized by the presence of bioactive constituents, particularly prenylated benzoic acid derivatives. In this study, the inhibitory potential of chemical constituents from P. cumanense and some synthesized compounds was determined on digestive enzymes (pancreatic lipase (PL) and α-glucosidase (AG)). The methodology included isolating and identifying secondary metabolites from P. cumanense, synthesizing some analogs, and a molecular docking study. The chemical study allowed the isolation of four prenylated benzoic acid derivatives (1-4). Four analogs (5-8) were synthesized. Seven compounds were found to significantly inhibit the catalytic activity of PL with IC50 values between 28.32 and 55.8 µM. On the other hand, only two compounds (6 and 7) were active as inhibitors of AG with IC50 values lower than 155 µM, standing out as the potential multitarget of these chromane compounds. Enzyme kinetics and molecular docking studies showed that the bioactive compounds mainly interact with amino acids other than those of the catalytic site in both PL and AG. This work constitutes the first report on the antidiabetic and antiobesity potential of substances derived from P. cumanense.
RESUMO
Digestive enzymes such α-amylase (AA), α-glucosidase (AG) and pancreatic lipase (PL), play an important role in the metabolism of carbohydrates and lipids, being attractive therapeutic targets for the treatment of type 2 diabetes and obesity. Garcinia mangostana is an interesting species because there have been identified xanthones with the potential to inhibit these enzymes. In this study, the multitarget inhibitory potential of xanthones from G. mangostana against AA, AG and PL was assessed. The methodology included the isolation and identification of bioactive xanthones, the synthesis of some derivatives and a molecular docking study. The chemical study allowed the isolation of five xanthones (1-5). Six derivatives (6-11) were synthesized from the major compound, highlighting the proposal of a new solvent-free methodology with microwave irradiation for obtaining aromatic compounds with tetrahydropyran cycle. Compounds with multitarget activity correspond to 2, 4, 5, 6 and 9, highlighting 6 with IC50 values of 33.3 µM on AA, 69.2 µM on AG and 164.4 µM on PL. Enzymatic kinetics and molecular docking studies showed that the bioactive xanthones are mainly competitive inhibitors on AA, mixed inhibitors on AG and non-competitive inhibitors on PL. The molecular coupling study established that the presence of methoxy, hydroxyl and carbonyl groups are important in the activity and interaction of polyfunctional xanthones, highlighting their importance depending on the mode of inhibition.
Assuntos
Diabetes Mellitus Tipo 2 , Garcinia mangostana , Xantonas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Garcinia mangostana/química , Lipase , Simulação de Acoplamento Molecular , Xantonas/química , alfa-Amilases , alfa-GlucosidasesRESUMO
Introducción: la enfermedad de Chagas es endémica de las zonas tropicales de América Latina y presenta una importante prevalencia, sin embargo, existen pocos tratamientos disponibles en el mercado por lo que la búsqueda de moléculas con potencial farmacológico que actúen en el parásito Trypanosoma cruzi, causante de la enfermedad, es necesaria considerando las graves complicaciones. Objetivo: evaluar las potenciales proteínas blanco, disponibles en la base de datos de PDB considerando como parámetro inicial, la similitud con proteínas humanas e identificar potenciales inhibidores del blanco elegido por medio de acoplamiento molecular. Metodología: se realizó una evaluación de las proteínas del parásito por medio de alineamiento de secuencias y posteriormente un cribado virtual por acoplamiento molecular con bases de datos y recursos informáticos disponibles en el Centro de Cómputo Avanzado de la Universidad de Texas (TACC), y se evaluaron los mejores resultados en función de afinidad, farmacocinética y toxicidad. Resultados: el blanco molecular elegido fue la dUTPasa. Posterior al cribado virtual se seleccionaron 12 moléculas que presentan potencial inhibidor de estas, la 4-{3-[3-(trifluorometil)fenil]isoxazol-5-il}pirimidin-2-amina es una de las moléculas con mejor perfil para convertirse en candidato en el tratamiento de la enfermedad de Chagas.
SUMMARY Introduction: Chagas disease is endemic to the tropical areas of Latin America and has an important prevalence, however, there are few treatments available in the market, so the search for molecules with pharmacological potential that can act in the same way as the disease, it is necessary considering the serious complications. Aim: to evaluate the possible target proteins available in the PDB database, considering the similarity with human proteins as an initial parameter and identify potential inhibitors of the chosen target using molecular docking. Methodology: an evaluation of the parasite proteins was carried out by means of sequence alignment and subsequently a virtual molecular coupling screening was performed with databases and computer resources available at Centro de Cómputo Avanzado de Universidad de Texas (TACC), and the best results were evaluated based on affinity, pharmacokinetics, and toxicity. Results: the molecular target chosen was the dUTPase. After virtual screening, 12 moles showing inhibitory potential were selected of these, 4- {3-[3- (trifluoromethyl) phenyl] isoxazole-5-yl} pyrimidine-2-amine is one of the molecules with the best profile to become a candidate in the treatment of Chagas disease.
Introdução: a doença de Chagas é endêmica das áreas tropicais da América Latina e possui importante prevalência, porém, poucos são os tratamentos disponíveis no mercado, por isso a busca por moléculas com potencial farmacológico que possam atuar da mesma forma que a doença, é necessário considerando as complicações graves. Objetivo: avaliar as possíveis proteínas-alvo disponíveis na base de dados do PDB, considerando a similaridade com proteínas humanas como parâmetro inicial e identificação de potenciais inibidores do alvo escolhido por meio de acoplamento molecular. Metodologia: uma avaliação das proteínas do parasita foi realizada por meio de alinhamento de sequências e posteriormente foi realizada uma triagem de acoplamento molecular virtual com bancos de dados e recursos computacionais disponíveis no Centro de Cómputo Avanzado de Universidad de Texas (TACC), e os melhores resultados foram avaliados com base na afinidade, farmacocinética e toxicidade. Resultados: o alvo molecular escolhido foi a dUTPase. Após a triagem virtual, 12 moles mostrando potencial inibitório foram selecionados destes, 4- {3- [3- (trifluorometil) fenil] isoxazol-5-il} pirimidina-2-amina é uma das moléculas com o melhor perfil para se tornar um candidato no tratamento da doença de Chagas.
RESUMO
Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane-binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.
Assuntos
Antozoários/química , Antineoplásicos/química , Produtos Biológicos/química , Misturas Complexas/química , Diterpenos/química , Bibliotecas de Moléculas Pequenas/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Misturas Complexas/farmacologia , Biologia Computacional , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Halogenação , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The emergence of tuberculosis (TB) produced by multi-drug resistance (MDR) and extensively-drug resistance (XDR) Mycobacterium tuberculosis (Mtb), encourages the development of new antituberculous compounds, as well as the identification of novel drug targets. In this regard, plasma membrane P-type ATPases are interesting targets because they play a crucial role in ion homeostasis and mycobacterial survival. We focused on Mtb CtpF, a calcium P-type ATPase that responds to a broad number of intraphagosomal conditions, as a novel target. In this study, we evaluated the capacity of cyclopiazonic acid (CPA), a well-known inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), to inhibit the ATPase activity of CtpF and the Mtb growth demonstrating that CtpF is a druggable target. A homology modeling of CtpF was generated for molecular docking studies of CtpF with CPA and key pharmacophoric features were identified, which were used to perform a pharmacophore-based virtual screening of the ZINC database, and to identify CtpF inhibitor candidates. Molecular docking-based virtual screening and MM-BGSA calculations of candidates allowed identifying six compounds with the best binding energies. The compounds displayed in vitro minimum inhibitory concentrations (MIC) ranging from 50 to 100 µg/mL, growth inhibitions from 29.5 to 64.0% on Mtb, and inhibitions of Ca2+-dependent ATPase activity in Mtb membrane vesicles (IC50) ranging from 4.1 to 35.8 µM. The compound ZINC63908257 was the best candidate by displaying a MIC of 50 µg/mL and a Ca2+ P-type ATPase inhibition of 45% with IC50 = 4.4 µM. Overall, the results indicate that CtpF is a druggable target for designing new antituberculous compounds.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-AtividadeRESUMO
The new psychoactive substances (NPS) in Colombia are detected by national authorities, in blotters strip, in different circumstances and places: airports, music concerts, discos and parks. Blotters are marketed as LSD and cause several cases of intoxication and death in some consumers: due to acute intoxication or when mixed with other drugs and may have different effects on the central nervous system (CNS). This study was conducted to research into and identify the chemical composition of the drugs impregnated in the blotters sold in two Colombian cities. This research provides the analysis of 70 doses coming from forensic cases of the Colombian Attorney General's Office in Bogota and from the Laboratory of Narcotics of the Colombian National Institute of Legal Medicine and Forensic Sciences (North Headquarter) in Barranquilla. Mixtures of drugs, such as DOB, 25I-NBOMe, MDMA and 25I-NBOMe imine were found within the blotters through gas chromatography coupled to mass spectrometry (CGMS); these drugs are classified by international authorities as NPS belonging to the phenylethylamines group. The results clearly warn about a growing public health problem in the country.
Assuntos
2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , Dimetoxifeniletilamina/análogos & derivados , Tráfico de Drogas , Drogas Ilícitas/isolamento & purificação , N-Metil-3,4-Metilenodioxianfetamina/isolamento & purificação , 2,5-Dimetoxi-4-Metilanfetamina/isolamento & purificação , Administração Sublingual , Colômbia , Drogas Desenhadas/isolamento & purificação , Dimetoxifeniletilamina/isolamento & purificação , Contaminação de Medicamentos , Humanos , Papel , Transtornos Relacionados ao Uso de SubstânciasRESUMO
X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A-C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists.
RESUMO
Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti-P-type ATPase activity. Furthermore, compounds that experimentally display anti-P-type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug-like) for evaluation as potential anti-TB drugs.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Descoberta de Drogas/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , ATPases Translocadoras de Prótons/antagonistas & inibidores , Tuberculose/tratamento farmacológico , Animais , Simulação por Computador , Desenho Assistido por Computador , Humanos , ATPases Translocadoras de Prótons/metabolismo , Relação Quantitativa Estrutura-Atividade , Tuberculose/microbiologiaRESUMO
The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE.
Assuntos
Sulfeto de Hidrogênio/agonistas , Óxido Nítrico/agonistas , Prunus avium/química , Triterpenos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Alcinos/antagonistas & inibidores , Alcinos/farmacologia , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , GMP Cíclico/metabolismo , Cistationina gama-Liase/química , Cistationina gama-Liase/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Frutas/química , Glibureto/antagonistas & inibidores , Glibureto/farmacologia , Glicina/análogos & derivados , Glicina/antagonistas & inibidores , Glicina/farmacologia , Sulfeto de Hidrogênio/metabolismo , Canais KATP/agonistas , Canais KATP/metabolismo , Masculino , Simulação de Acoplamento Molecular , NG-Nitroarginina Metil Éster/antagonistas & inibidores , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/química , Óxido Nítrico Sintase Tipo III/metabolismo , Extratos Vegetais/química , Ligação Proteica , Ratos , Triterpenos/isolamento & purificação , Vasodilatadores/isolamento & purificação , Ácido UrsólicoRESUMO
Bioactive food compounds can be both therapeutically and nutritionally relevant. Screening strategies are widely employed to identify bioactive compounds from edible plants. Flavor additives contained in the so-called FEMA GRAS (generally recognized as safe) list of approved flavoring ingredients is an additional source of potentially bioactive compounds. This work used the principles of molecular similarity to identify compounds with potential mood-modulating properties. The ability of certain GRAS molecules to inhibit histone deacetylase-1 (HDAC1), proposed as an important player in mood modulation, was assayed. Two GRAS chemicals were identified as HDAC1 inhibitors in the micromolar range, results similar to what was observed for the structurally related mood prescription drug valproic acid. Additional studies on bioavailability, toxicity at higher concentrations, and off-target effects are warranted. The methodology described in this work could be employed to identify potentially bioactive flavor chemicals present in the FEMA GRAS list.
Assuntos
Aromatizantes/química , Extratos Vegetais/química , Plantas Comestíveis/química , Antidepressivos/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Histona Desacetilase 1/antagonistas & inibidores , Estrutura MolecularRESUMO
A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 µM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11ß-HSD1. In this model, compound 1 binds into the catalytic site of 11ß-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).
Assuntos
Ácido Clofíbrico/química , Hipoglicemiantes/síntese química , Tetrazóis/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Sítios de Ligação , Glicemia/análise , Domínio Catalítico , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/uso terapêuticoRESUMO
Morolic (1) and moronic (2) acids are the main constituents of acetonic extract from Phoradendron reichenbachianum (Loranthaceae), a medicinal plant used in Mexico for the treatment of diabetes. The aim of the current study was to establish the sub-acute antidiabetic and antihyperlipidemic effects of compounds 1 and 2 over non insulin-dependent diabetic rat model. Also, to determine the antihyperglycemic action on normoglycemic rats by oral glucose tolerance test. Daily-administered morolic (1) and moronic (2) acids (50 mg/kg) significantly lowered the blood glucose levels at 60% since first day until tenth day after treatment than untreated group (p<0.05). Moreover, analyzed blood samples obtained from diabetic rats indicated that both compounds diminished plasmatic concentration of cholesterol (CHO) and triglycerides (TG), returning them to normal levels (p<0.05). Also, pretreatment with 50 mg/kg of each compound induced significant antihyperglycemic effect after glucose and sucrose loading (2 g/kg) compared with control group (p<0.05). In vitro studies showed that compounds 1 and 2 induced inhibition of 11ß-HSD 1 activity at 10 µM. However, in silico analysis of the pentaclyclic triterpenic acids on 11ß-HSD 1 revealed that all compounds had high docking scores and important interactions with the catalytic site allowing them to inhibit 11ß-HSD 1 enzyme. In conclusion, morolic and moronic acids have shown sustained antidiabetic and antihyperglycemic action possibly mediated by an insulin sensitization with consequent changes of glucose, cholesterol and triglycerides, in part mediated by inhibition of 11ß-HSD 1 as indicated by in vitro and in silico studies.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Ácido Oleanólico/análogos & derivados , Triterpenos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Glicemia/análise , Colesterol/sangue , Simulação por Computador , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Teste de Tolerância a Glucose , Células HEK293/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ratos , Ratos Wistar , Triglicerídeos/sangue , Triterpenos/químicaRESUMO
The aim of the current study was to investigate the vasorelaxant activity of five structurally-related triterpenic acids namely ursolic (1), moronic (2), morolic (3), betulinic (4) and 3,4-seco-olean-18-ene-3,28-dioic (5) acids. The vasorelaxant effect of compounds 1-5 were determined on endothelium-denuded and endothelium-intact rat aortic rings pre-contracted with noradrenaline (0.1 µM). All compounds showed significant relaxant effect on endothelium-intact vessels in a concentration-dependent manner (p<0.05). Ursolic, moronic and betulinic acids were the most potent vasorelaxant agents with 11.7, 16.11 and 58.46 µM, respectively. Since vasorelaxation was blocked by L-NAME, while indomethacin did not inhibit the effect, endothelium-derived nitric oxide seems to be involved in triterpenic 2 and 3 mode of action. Compounds 1-5 were docked with a crystal structure of eNOS. Triterpenes 1-5 showed calculated affinity with eNOS in the C1 and C2 binding pockets, near the catalytic site; Ser248 and Asp480 are the residues that make hydrogen bonds with the triterpene compounds.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Óxido Nítrico/biossíntese , Phoradendron/química , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta , Relação Dose-Resposta a Droga , Ligação de Hidrogênio , Indometacina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Extratos Vegetais/química , Ratos , Triterpenos/isolamento & purificação , Vasodilatadores/isolamento & purificaçãoRESUMO
The ethyl 2-(6-substituted benzo[d]thiazol-2-ylamino)-2-oxoacetate derivatives (OX 1-9) were prepared using a one-step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds OX-(1, 6 and 7) were rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micro-molar range. The most active compounds OX-(1, 6 and 7) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the oxamate group in all compounds and the catalytic amino acid residues Arg221 and Ser216. The compounds were evaluated for their in vivo hypoglycemic activity, showing significant lowering of plasma glucose concentration in acute normoglycemic model and oral glucose tolerance test similarly at the effect exerted for hypoglycemic drug glibenclamide.
Assuntos
Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Biologia Computacional , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Benzotiazóis/química , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Modelos Moleculares , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Ratos , Ratos WistarRESUMO
The aim of the current study was to investigate the oral antidiabetic activity of four structurally-related triterpenic acids: ursolic (RE-01), oleanolic (RE-02), moronic (RE-03) and morolic (RE-04) acids. STZ-nicotinamide diabetic rats were treated with these triterpenes (50 mg/kg) and the antidiabetic effects in acute experiment were determined. All compounds showed significant antidiabetic activity in comparison with control group (p<0.05). The in vitro inhibitory activity of compounds against protein tyrosine phosphatase 1B (PTP-1B) was also evaluated. At 50 µM, the enzymatic activity was almost completely inhibited. All compounds were docked with a crystal structure of PTP-1B. Docking results suggested the potential binding of the triterpenic acids in a binding pocket next to the catalytic site. An extensive hydrogen bond network with the carboxyl group and Van der Waals interactions stabilize the protein-ligand complexes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Diabetes Mellitus Experimental/enzimologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/química , Masculino , Modelos Moleculares , Conformação Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/isolamento & purificação , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
The purpose of this work is to study the molecular association that occurs between 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20), an antiparasitic compound recently found by our research group, with poor aqueous solubility. The complex stability constant and stoichiometric ratio determined by phase-solubility diagram and Job's plot provided evidence that HPßCD enhanced water solubility of RCB20 through inclusion complex formation. Two-dimensional ¹H NMR spectroscopy is used to study the molecular arrangement of inclusion complex in solution. These results are further supported using molecular modeling studies. In the solid state, the complexation is confirmed by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. Finally, RCB20/HPßCD complex has better activity than RCB20 against the adult and muscle larvae phase of Trichinella spiralis.
Assuntos
Anti-Helmínticos/química , Benzimidazóis/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Varredura Diferencial de Calorimetria , Modelos Animais de Doenças , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Triquinelose/tratamento farmacológico , Difração de Raios XRESUMO
The structural reassignment, absolute configuration, and conformational behavior of the highly flexible natural product hypurticin (pectinolide E), 6S-[3'S,5'R,6'S-triacetoxy-1Z-heptenyl]-5S-acetoxy-5,6-dihydro-2H-pyran-2-one (1), were ascertained by a molecular modeling protocol, which includes extensive conformational searching, geometry optimization by DFT B3LYP/DGDZVP calculations, and comparison between the theoretical (DFT) and experimental (1)H-(1)H NMR coupling constants. Hyptolide (2), a related cytotoxic 5,6-dihydro-2H-pyran-2-one that increased the S phase of the HeLa cell cycle, was employed as a reference substance to validate the theoretical protocol designed to characterize the 3D properties of compound 1. The related synthetic derivative, tri-O-acetyl-3,6-dideoxy-d-glucose diphenyldithioacetal (14), was prepared by a six-step reaction sequence starting from d-glucose and served as an enantiopure building block to reinforce the structural and configurational assignment of 1. This protocol proved to be an important tool for the structural characterization of highly flexible bioactive polyoxygenated natural products.
Assuntos
Modelos Moleculares , Pironas/química , Algoritmos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glucose/química , Células HeLa , Humanos , Conformação Molecular , Estrutura Molecular , Pironas/isolamento & purificação , Pironas/farmacologia , EstereoisomerismoRESUMO
Comparative molecular field analysis (CoMFA) was performed on a set of 1H-benzimidazole derivatives. Molecular modeling and 3D-QSAR were employed to determine the tautomeric form that would probably fit a target receptor in Entamoeba histolytica. CoMFA results suggest that the antiamoebic activity is favored with steric bulk at position 5 of the benzimidazole ring and low electron density on the group at position 2. To the best of our knowledge this is the first 3D-QSAR study performed for benzimidazoles as antiamoebic agents. The CoMFA models derived will be very valuable to design new and more potent compounds against E. histolytica.
Assuntos
Amebicidas/síntese química , Amebicidas/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Algoritmos , Animais , Análise dos Mínimos Quadrados , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos TestesRESUMO
Docking experiments using a number of published crystal structures of HMG-CoA reductase with the potent hypocholesterolemic agent alpha-asarone are described. The results indicate that alpha-asarone binds in the enzyme's active site. The methoxy groups play a key role in the binding and probably also in its biological activity, as shown by extensive SAR studies reported for analogues of alpha-asarone. The docking results will be valuable for the structure-based design of novel hypolipidemic agents.