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1.
Int Immunopharmacol ; 99: 107923, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34229177

RESUMO

Our previous research demonstrated that compound licochalcone E can reduce glucose tolerance and lipid metabolism in diabetic rats, although its mechanism remains unknown. Here, we used palmitic acid (PA) to establish a PA-treated HepG2 model, and then examined glucose uptake, glucose consumption, and blood lipids to evaluate the effects of licochalcone E within the safe dose range in the model. Polymerase chain reaction (PCR) was used to detect the expression levels of key genes associated with liver gluconeogenesis; enzyme-linked immunosorbent assay (ELISA) was deployed to evaluate the concentration of inflammatory factors; and laser confocal microscopy and western blot were used to determine the levels of reactive oxygen species (ROS) and NLRP3 inflammasome signaling pathway-related proteins, respectively. Finally, molecular simulations were exploited to validate the interaction between licochalcone E and the NLRP3 inflammasome. The results demonstrated that licochalcone E showed no toxicity in the dose range of 2.5-40 µM. In this dose range, licochalcone E substantially increased the uptake and consumption of glucose in the insulin resistance model and dose-dependently reduced the concentration of total cholesterol. The PCR results indicated that licochalcone E dose-dependently reduced the expression of Glucose-6-phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (PEPCK) genes and increased the expression of Glucose Transporter 4 (Glut4) in PA-treated HepG2. Moreover, the ELISA results revealed that licochalcone E significantly reduced the expression of TNF-α, IL-1ß, and IL-18. Confocal microscopy results showed that licochalcone E dramatically reduced the generation of ROS and the expressions of NLRP3 and its downstream caspase-1 in PA-treated HepG2 model. Western blot results further indicated that licochalcone E significantly reduced the expression of NLRP3, caspase-1 and IL-1ß in the model. Additionally, molecular simulations demonstrated that licochalcone E has good binding affinity for the NLPR3 inflammasome. We concluded that licochalcone E has the potential to be used as an insulin sensitizer by reducing the release of ROS and inflammatory factors following inhibition of the NLPR3 signaling pathway.


Assuntos
Chalconas/farmacologia , Inflamassomos/antagonistas & inibidores , Resistência à Insulina , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Glucose/metabolismo , Células Hep G2 , Humanos , Inflamassomos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Palmítico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Biomol Ther (Seoul) ; 29(4): 392-398, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34053940

RESUMO

8K: and a serotonin/norepinephrine reuptake inhibitor. 7J: showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound. 8K: bound tightly to the binding pocket of all three monoamine reuptake transporters; however. 7J: showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with. 8F: , which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

3.
Bioorg Med Chem ; 27(6): 963-977, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737132

RESUMO

We describe herein the design, synthesis, and biological evaluation of a series of novel protein tyrosine phosphatase 1B (PTP1B) inhibitor retrochalcones having an allyl chain at the C-5 position of their B ring. Biological screening results showed that the majority of these compounds exhibited an inhibitory activity against PTP1B. Thus, preliminary structure-activity relationship (SAR) and quantitative SAR analyses were conducted. Among the compounds, 23 was the most potent inhibitor, exhibiting the highest in vitro inhibitory activity against PTP1B with an IC50 of 0.57 µM. Moreover, it displayed a significant hepatoprotective property via activation of the IR pathway in type 2 diabetic db/db mice. In addition, the results of our docking study showed that 23, as a specific inhibitor of PTP1B, effectively transformed the WPD loop from "close" to "open" in the active site. These results may reveal suitable compounds for the development of PTP1B inhibitors.


Assuntos
Chalconas/química , Chalconas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Compostos Alílicos/síntese química , Compostos Alílicos/química , Compostos Alílicos/farmacologia , Animais , Chalconas/síntese química , Inibidores Enzimáticos/síntese química , Células Hep G2 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Quantitativa Estrutura-Atividade , Ratos Sprague-Dawley
4.
Medchemcomm ; 9(9): 1457-1465, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288220

RESUMO

The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2R and D3R have rendered the development of D3R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D3R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.

6.
Bioorg Med Chem ; 26(20): 5538-5546, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30293797

RESUMO

Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.


Assuntos
Piperazina/análogos & derivados , Piperazina/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/química , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Desenho de Fármacos , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Norepinefrina/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
8.
Bioorg Med Chem ; 25(20): 5278-5289, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28807575

RESUMO

Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine-tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.


Assuntos
Desenho de Fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Piperidinas/farmacologia , Tetrazóis/farmacologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/química , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Piperidinas/síntese química , Piperidinas/química , Serotonina/metabolismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
9.
Bioorg Med Chem ; 25(7): 2266-2276, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28274674

RESUMO

Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50=158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.


Assuntos
Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Células HEK293 , Humanos , Técnicas In Vitro , Inibidores da Captação de Neurotransmissores/síntese química , Piperazinas/síntese química , Piperidinas/síntese química
10.
Chem Biol Interact ; 268: 24-30, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28242381

RESUMO

In this study, we aimed to demonstrate the antidiabetic potential of (E)-N-(4-(3-(5-bromo-4-hydroxy-2-methoxyphenyl)acryloyl) phenyl)-4-tert-butylbenzamide (SN158) through peroxisome proliferator-activated receptor (PPAR)-α/γ dual activation. SN158 interacted with both PPARα and PPARγ, and increased their transcriptional activities. Simultaneously, SN158 treatment led to an increase in adipogenic differentiation of 3T3-L1 preadipocytes and fatty acid oxidation in hepatocytes. In addition, glucose uptake in myotubes was significantly increased by SN158 treatment. Finally, SN158 significantly lowered the plasma levels of glucose, triglycerides, and free fatty acids in ob/ob mice without severe weight gain and hepatomegaly. These results suggest that SN158 can be useful as a potential therapeutic agent against type 2 diabetes and related metabolic disorders by alleviating glucose and lipid abnormalities.


Assuntos
Benzamidas/farmacologia , Chalconas/farmacologia , Hipoglicemiantes/farmacologia , PPAR alfa/agonistas , PPAR delta/agonistas , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adiponectina/genética , Animais , Benzamidas/administração & dosagem , Glicemia/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Carnitina O-Palmitoiltransferase/metabolismo , Diferenciação Celular/efeitos dos fármacos , Chalconas/administração & dosagem , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/sangue , Hipoglicemiantes/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Oxirredutases/metabolismo , Pioglitazona , RNA Mensageiro/metabolismo , Estereoisomerismo , Tiazolidinedionas/farmacologia , Transcrição Gênica , Triglicerídeos/sangue
11.
Bioorg Med Chem ; 24(21): 5546-5555, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27647372

RESUMO

In the search for potent dual norepinephrine and dopamine reuptake inhibitors, several substituted arylpiperazine-tetrazoles were designed, synthesized and evaluated for their neurotransmitter reuptake inhibitory activities. Various derivatives exhibited selective and strong neurotransmitter reuptake inhibitory activity. In particular, compounds with a three-carbon linker displayed selective and stronger potency than those with two-carbon and four-carbon linkers. Interestingly, six compounds, 9b, 9c, 9d, 9o, 9q and 9u displayed more effective activity than the standard drug, bupropion. The provided SAR data and potent biological activity can offer useful guidelines for designing dual norepinephrine and dopamine reuptake inhibitors as effective therapeutic agents for treatment of several central nervous system diseases.


Assuntos
Dopamina/metabolismo , Norepinefrina/antagonistas & inibidores , Piperazinas/farmacologia , Tetrazóis/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Norepinefrina/metabolismo , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
12.
Bioorg Med Chem ; 24(9): 2137-45, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27041397

RESUMO

The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine-benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC50=0.38 µM for NE and 1.18 µM for 5-HT). The biological activity data demonstrate that arylpiperazine-benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Células HEK293 , Humanos
13.
Biochim Biophys Acta ; 1863(1): 77-90, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26477566

RESUMO

GTP binding proteins are classified into two families: heterotrimeric large G proteins which are composed of three subunits, and one subunit of small G proteins. Roles of small G proteins in the intracellular trafficking of G protein-coupled receptors (GPCRs) were studied. Among various small G proteins tested, GTP-bound form (G23V) of RalA inhibited the internalization of dopamine D2 receptor independently of the previously reported downstream effectors of RalA, such as Ral-binding protein 1 and PLD. With high affinity for GRK2, active RalA inhibited the GPCR endocytosis by sequestering the GRK2 from receptors. When it was tested for several GPCRs including an endogenous GPCR, lysophosphatidic acid receptor 1, agonist-induced conversion of GTP-bound to GDP-bound RalA, which presumably releases the sequestered GRK2, was observed selectively with the GPCRs which have tendency to undergo endocytosis. Conversion of RalA from active to inactive state occurred by translocation of RGL, a guanine nucleotide exchange factor, from the plasma membrane to cytosol as a complex with Gßγ. These results suggest that agonist-induced Gßγ-mediated conversion of RalA from the GTP-bound form to the GDP-bound form could be a mechanism to facilitate agonist-induced internalization of GPCRs.


Assuntos
Endocitose/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Ácidos Lisofosfatídicos/agonistas , Proteínas ral de Ligação ao GTP/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/genética , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Células HEK293 , Humanos , Transporte Proteico/fisiologia , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Proteínas ral de Ligação ao GTP/genética
14.
Bioorg Med Chem ; 24(2): 191-200, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26707842

RESUMO

The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R.


Assuntos
Desenho de Fármacos , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D3/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Piperazinas/síntese química , Piperazinas/química , Receptores de Dopamina D2/metabolismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 23(19): 6418-26, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26337019
16.
Bioorg Med Chem ; 23(17): 5264-72, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26278029

RESUMO

The dopamine D3 receptor (D3R) preferential ligands have been universally adopted as a strategy for the treatment of drug addiction and other neuropsychiatric disorders due to fewer side effects. However, the high sequence homology between D3R and the D2 receptor (D2R) challenges the development of D3R-biased compounds. Herein, we design and synthesize a novel series of reverse amide-piperazine hybrid ligands and evaluate their biological affinities in vitro. Compound 4d was found to be the most potent D3R-selective ligand among these hybrid derivatives. Molecular modeling revealed that extracellular loop 1 (EL1) and loop 2 (EL2) of D3R together likely contribute to D3R selectivity over D2R. In particular, Gly94 in EL1 of D3R may act as a molecular determinant for D3R specificity.


Assuntos
Amidas/química , Amidas/farmacologia , Desenho de Fármacos , Piperazinas/química , Piperazinas/farmacologia , Receptores de Dopamina D3/metabolismo , Sítios de Ligação , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Piperazina , Receptores de Dopamina D3/química , Relação Estrutura-Atividade
17.
Biochim Biophys Acta ; 1848(10 Pt A): 2101-10, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26055893

RESUMO

Among the multiple G protein-coupled receptor (GPCR) endocytic pathways, clathrin-mediated endocytosis (CME) and caveolar endocytosis are more extensively characterized than other endocytic pathways. A number of endocytic inhibitors have been used to block CME; however, systemic studies to determine the selectivity of these inhibitors are needed. Clathrin heavy chain or caveolin1-knockdown cells have been employed to determine the specificity of various chemical and molecular biological tools for CME and caveolar endocytosis. Sucrose, concanavalin A, and dominant negative mutants of dynamin blocked other endocytic pathways, in addition to CME. In particular, concanavalin A nonspecifically interfered with the signaling of several GPCRs tested in the study. Decreased pH, monodansylcadaverine, and dominant negative mutants of epsin were more specific for CME than other treatments were. A recently introduced CME inhibitor, Pitstop2™, showed only marginal selectivity for CME and interfered with receptor expression on the cell surface. Blockade of receptor endocytosis by epsin mutants and knockdown of the clathrin heavy chain enhanced the ß2AR-mediated ERK activation. Overall, our studies show that previous experimental results should be interpreted with discretion if they included the use of endocytic inhibitors that were previously thought to be CME-selective. In addition, our study shows that endocytosis of ß2 adrenoceptor through clathrin-mediated pathway has negative effects on ERK activation.


Assuntos
Cavéolas/metabolismo , Clatrina/metabolismo , Endocitose/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Sulfonamidas/administração & dosagem , Tiazolidinas/administração & dosagem , Animais , Células COS , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Endocitose/efeitos dos fármacos , Células HEK293 , Humanos , Receptores Acoplados a Proteínas G/antagonistas & inibidores
18.
Biochim Biophys Acta ; 1853(1): 41-51, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25289757

RESUMO

Numerous G protein-coupled receptors (GPCRs) are glycosylated at extracellular regions. The regulatory roles of glycosylation on receptor function vary across receptor types. In this study, we used the dopamine D2and D3receptors as an experimental model to understand the underlying principles governing the functional roles of glycosylation. We used the pharmacological inhibitor, tunicamycin, to inhibit glycosylation, generated chimeric D2and D3receptors by swapping their respective N-termini, and produced the glycosylation site mutant D2and D3receptors to study the roles of glycosylation on receptor functions, including cell surface expression, signaling, and internalization through specific microdomains. Our results demonstrate that glycosylation on the N-terminus of the D3 receptor is involved in the development of desensitization and proper cell surface expression. In addition, glycosylation on the N-terminus mediates the internalization of D2and D3receptors within the caveolae and clathrin-coated pit microdomains of the plasma membrane, respectively, by regulating receptor interactions with caveolin-1 and clathrin. In conclusion, this study shows for the first time that glycosylation on the N-terminus of GPCRs is involved in endocytic pathway selection through specific microdomains. These data suggest that changes in the cellular environment that influence posttranslational modification could be an important determinant of intracellular GPCR trafficking.


Assuntos
Microdomínios da Membrana/química , Receptores de Dopamina D2/química , Receptores de Dopamina D3/química , Sequência de Aminoácidos , Endocitose , Glicosilação , Células HEK293 , Humanos , Dados de Sequência Molecular , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Tunicamicina/farmacologia
19.
Bioorg Med Chem Lett ; 24(15): 3234-7, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24974340
20.
Bioorg Med Chem Lett ; 24(15): 3337-40, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24953600

RESUMO

A series of novel 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives was designed, and synthesized based on our previous studies. Also their activities were evaluated as competitive inhibitors of protein tyrosine phosphatase 1B (PTP1B). Compounds 6d-6g, 7b, 7c, 7e, 7j, 7k, 7m, 14b and 14e-14f showed potent inhibitory effects against PTP1B, and compound 7e, the most potent among the series, had an IC50 of 4.6 µM. Also a Surflex-Dock docking model of 7e was studied. Compound 7e showed a negative binding energy of -7.35 kcal/mol and a high affinity to PTP1B residues (Gly220, Ala217, Arg221, Asp181, Ser216, Cys215, Phe182, Gln262 and Ile219) in the active sites, indicating that it may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
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