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1.
Int J Mol Sci ; 21(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046006

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid ß-peptide (Aß) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of Aß. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the α-sheet structure in Aß drives aggregation and toxicity in AD. However, how the α-sheet structure is formed in Aß and how it contributes to Aß aggregation remains elusive. In the present study, molecular dynamics simulations suggest that Aß adopts the α-strand conformation by peptide-plane flipping. Multiple α-strands interact through hydrogen bonding to form α-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of Aß. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the α-strand/α-sheet structure.

2.
Bioorg Med Chem Lett ; 30(2): 126787, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759849

RESUMO

The 11ß-hydroxysteroiddehydrogenase type 1(11ß-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11ß-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11ß-HSD1 and showed good 11ß-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11ß-HSD1 were suggested.

3.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374894

RESUMO

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis.


Assuntos
Desenho de Drogas , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Relação Estrutura-Atividade , Humanos , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/efeitos dos fármacos , Água/química
4.
Molecules ; 24(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336667

RESUMO

Water molecules play a key role in protein stability, folding, function and ligand binding. Protein hydration has been studied using free energy perturbation algorithms. However, the study of protein hydration without free energy calculation is also an active field of research. Accordingly, topological water network (TWN) analysis has been carried out instead of free energy calculation in the present work to investigate hydration of proteins. Water networks around 20 amino acids in the aqueous solution were explored through molecular dynamics (MD) simulations. These simulation results were compared with experimental observations. Water molecules from the protein data bank structures showed TWN patterns similar to MD simulations. This work revealed that TWNs are effected by the surrounding environment. TWNs could provide valuable clues about the environment around amino acid residues in the proteins. The findings from this study could be exploited for TWN-based drug discovery and development.


Assuntos
Aminoácidos/química , Água/química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
5.
Exp Mol Med ; 51(2): 12, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755593

RESUMO

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer's disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1 µM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE, and BChE indicated novel binding site-directed inhibition of the enzymes by pterosins and the structure-activity relationship. (2R)-Pterosin B exhibited a strong BBB permeability with an effective permeability (Pe) of 60.3×10-6 cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3 R)-pteroside C significantly decreased the secretion of Aß peptides from neuroblastoma cells that overexpressed human ß-amyloid precursor protein at 500 µM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.


Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Ligantes , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Permeabilidade , Proteínas Recombinantes , Relação Estrutura-Atividade
6.
Sci Rep ; 9(1): 59, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635607

RESUMO

The α-synuclein is a major component of amyloid fibrils found in Lewy bodies, the characteristic intracellular proteinaceous deposits which are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease (PD) and dementia. It is an intrinsically disordered protein that may undergo dramatic structural changes to form amyloid fibrils. Aggregation process from α-synuclein monomers to amyloid fibrils through oligomeric intermediates is considered as the disease-causative toxic mechanism. However, mechanism underlying aggregation is not well-known despite several attempts. To characterize the mechanism, we have explored the effects of pH and temperature on the structural properties of wild-type and mutant α-synuclein using molecular dynamics (MD) simulation technique. MD studies suggested that amyloid fibrils can grow by monomer. Conformational transformation of the natively unfolded protein into partially folded intermediate could be accountable for aggregation and fibrillation. An intermediate α-strand was observed in the hydrophobic non-amyloid-ß component (NAC) region of α-synuclein that could proceed to α-sheet and initiate early assembly events. Water network around the intermediate was analyzed to determine its influence on the α-strand structure. Findings of this study provide novel insights into possible mechanism of α-synuclein aggregation and promising neuroprotective strategy that could aid alleviate PD and its symptoms.

7.
J Pharm Biomed Anal ; 164: 590-597, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30469108

RESUMO

The antioxidant enzyme human extracellular superoxide dismutase (SOD3) is a promising biopharmaceutical candidate for the treatment of various diseases. To support the early development of SOD3 as a biopharmaceutical, a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry procedure was developed and validated for the determination of SOD3 levels in the plasma of ICR mice. After purification with Ni-NTA magnetic beads and digestion with trypsin, SOD3 signature peptides and internal standard signature peptide (ISP) were separated via high performance liquid chromatography using a Zorbax C18 column (2.1 × 50 mm, 3.5 µm) and a mobile phase consisting of 10 mM ammonium formate, 0.1% formic acid, and acetonitrile. The analyte and ISP were detected via a tandem mass spectrometer in electrospray ionization and multiple reaction monitoring modes to select both the signature peptide for SOD3 at m/z 669 to 969 and the ISP at m/z 655 to 941 in the positive ion mode. The calibration curves were linear (r > 0.99) between 5 and 1000 µg/mL with a lower limit of quantification of 5 µg/mL. The relative standard deviation ranged from 3.08 to 8.84% while the relative error ranged from -0.13 to -9.56%. This method was successfully applied to a preclinical pharmacokinetic study of SOD3 in male ICR mice.


Assuntos
Produtos Biológicos/farmacocinética , Fracionamento Químico/métodos , Superóxido Dismutase/farmacocinética , Animais , Produtos Biológicos/sangue , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Células HEK293 , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Peptídeos/sangue , Peptídeos/isolamento & purificação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacocinética , Padrões de Referência , Reprodutibilidade dos Testes , Organismos Livres de Patógenos Específicos , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/sangue , Superóxido Dismutase/isolamento & purificação , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
8.
Molecules ; 23(12)2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30501110

RESUMO

Protein kinases are deeply involved in immune-related diseases and various cancers. They are a potential target for structure-based drug discovery, since the general structure and characteristics of kinase domains are relatively well-known. However, the ATP binding sites in protein kinases, which serve as target sites, are highly conserved, and thus it is difficult to develop selective kinase inhibitors. To resolve this problem, we performed molecular dynamics simulations on 26 kinases in the aqueous solution, and analyzed topological water networks (TWNs) in their ATP binding sites. Repositioning of a known kinase inhibitor in the ATP binding sites of kinases that exhibited a TWN similar to interleukin-1 receptor-associated kinase 4 (IRAK4) allowed us to identify a hit molecule. Another hit molecule was obtained from a commercial chemical library using pharmacophore-based virtual screening and molecular docking approaches. Pharmacophoric features of the hit molecules were hybridized to design a novel compound that inhibited IRAK4 at low nanomolar levels in the in vitro assay.


Assuntos
Desenho de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Água/química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Estaurosporina/química , Estaurosporina/farmacologia
9.
Molecules ; 23(3)2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29498658

RESUMO

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb-drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 µM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone-drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.


Assuntos
Benzopiranos/química , Citocromo P-450 CYP2B6/química , Citocromo P-450 CYP2C19/química , Citocromo P-450 CYP2E1/química , Citocromo P-450 CYP3A/química , Dioxóis/química , Interações Ervas-Drogas , Saururaceae/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/farmacologia , Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Sítios de Ligação , Domínio Catalítico , Clorzoxazona/química , Clorzoxazona/farmacologia , Clopidogrel , Ciclobutanos/química , Ciclobutanos/farmacologia , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/isolamento & purificação , Inibidores das Enzimas do Citocromo P-450/farmacologia , Dioxóis/isolamento & purificação , Dioxóis/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Cinética , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Simulação de Acoplamento Molecular , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Ticlopidina/análogos & derivados , Ticlopidina/química , Ticlopidina/farmacologia
10.
Eur J Med Chem ; 148: 397-409, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29477073

RESUMO

Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.


Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Antineoplásicos/química , Domínio Catalítico , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Ligação Proteica , Relação Estrutura-Atividade
11.
Exp Cell Res ; 359(1): 30-38, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28803066

RESUMO

In glaucoma, retinal ganglion cells (RGCs) are exposed to ischemic stress with elevation of the intraocular pressure and are subsequently lost. Necroptosis, a type of regulated necrosis, is known to play a pivotal role in this loss. We observed that receptor-interacting protein kinase 1 (RIPK1), the key player of necroptosis, was activated by diverse ischemic stresses, including TCZ, chemical hypoxia (CH), and oxygen glucose deprivation (OGD). In this study, we introduce a RIPK1-inhibitory compound (RIC) with a novel scaffold. RIC inhibited downstream events following RIPK1 activation, including necrosome formation and mitochondrial dysfunction in RGC5 cells. Moreover, RIC protected RGCs against ischemic injury in the rat glaucoma model, which was induced by acute high intraocular pressure. However, RIC displayed biochemical characteristics that are distinct from those of previous RIPK1 inhibitors (necrostatin-1; Nec-1 and Compound 27; Cpd27). RIC protected RGCs against OGD insult, while Nec-1 and Cpd27 did not. Conversely, Nec-1 and Cpd27 protected RGCs from TNF-stimulated death, while RIC failed to inhibit the death of RGCs. This implies that RIPK1 activates alternative pathways depending on the context of the ischemic insults.


Assuntos
Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Cicloeximida , Modelos Animais de Doenças , Glaucoma/complicações , Glaucoma/patologia , Glucose/deficiência , Células HT29 , Humanos , Injeções Intraperitoneais , Isquemia/complicações , Isquemia/patologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Necrose , Neuroproteção/efeitos dos fármacos , Oligopeptídeos , Oxigênio , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley , Degeneração Retiniana/complicações , Degeneração Retiniana/patologia , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Fator de Necrose Tumoral alfa
12.
Bioorg Med Chem Lett ; 27(17): 4156-4164, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28743508

RESUMO

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC50=2.99 and 2.19nM, respectively). Inhibitory activity of 21 was found to be slightly better than PF-8380 (IC50=2.80nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, 21 displayed higher potency (IC50=14.99nM) than the first clinical ATX inhibitor, GLPG1690 (IC50=242.00nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of 21 was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Diester Fosfórico Hidrolases/metabolismo , Tiazóis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
13.
Biochem Biophys Res Commun ; 484(2): 348-353, 2017 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-28131826

RESUMO

In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved, essential and non-disease, non-druggable genes compared to the peripheral genes. Overall, our study provides an insight into how all human cells share a common function and generate tissue-specific functional traits by transmitting and processing information through regulatory network.


Assuntos
Redes Reguladoras de Genes , Humanos , Biologia de Sistemas
14.
Eur J Med Chem ; 123: 777-787, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27541261

RESUMO

Wild type transthyretin (TTR) and mutant TTR misfold and misassemble into a variety of extracellular insoluble amyloid fibril and/or amorphous aggregate, which are associated with a variety of human amyloid diseases. To develop potent TTR amyloidogenesis inhibitors, we have designed and synthesized a focused library of quinoline derivatives by Pd-catalyzed coupling reaction and by the Horner-Wadsworth-Emmons reaction. The resulting 2-alkynylquinoline derivatives, (E)-2-alkenylquinoline derivatives, and (E)-3-alkenylquinoline derivatives were evaluated to inhibit TTR amyloidogenesis by utilizing the acid-mediated TTR fibril formation. Among these quinoline derivatives, compound 14c exhibited the most potent anti-TTR fibril formation activity in the screening studies, with IC50 values of 1.49 µM against WT-TTR and 1.63 µM against more amyloidogenic V30 M TTR mutant. That is comparable to that of approved therapeutic drug, tafamidis, to ameliorate transthyretin-related amyloidosis. Furthermore, rationalization of the increased efficacy of compound 14c bearing a hydrophobic substituent, such as chloride, was carried out by utilizing in silico docking study that could focus on the region of the thyroid hormone thyroxine (T4) binding sites. Additionally, the most potent compound 14c exhibited good pharmacokinetics properties. Taken together, the novel quinoline derivatives could potentially be explored as potential drug candidates to treat the human TTR amyloidosis.


Assuntos
Amiloide/química , Pré-Albumina/química , Agregados Proteicos/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Animais , Humanos , Masculino , Simulação de Acoplamento Molecular , Mutação , Pré-Albumina/genética , Pré-Albumina/metabolismo , Estrutura Secundária de Proteína/efeitos dos fármacos , Quinolinas/metabolismo , Ratos
15.
PLoS One ; 11(5): e0155432, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27176632

RESUMO

Lysimachia foenum-graecum extract (LFE) and its active component foenumoside B (FSB) have been shown to inhibit adipocyte differentiation, but their mechanisms were poorly defined. Here, we investigated the molecular mechanisms responsible for their anti-adipogenic effects. Both LFE and FSB inhibited the differentiation of 3T3-L1 preadipocytes induced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists, accompanied by reductions in the expressions of the lipogenic genes aP2, CD36, and FAS. Moreover, LFE and FSB inhibited PPARγ transactivation activity with IC50s of 22.5 µg/ml and 7.63 µg/ml, respectively, and showed selectivity against PPARα and PPARδ. Rosiglitazone-induced interaction between PPARγ ligand binding domain (LBD) and coactivator SRC-1 was blocked by LFE or FSB, whereas reduced NCoR-1 binding to PPARγ by rosiglitazone was reversed in the presence of LFE or FSB. In vivo administration of LFE into either ob/ob mice or KKAy mice reduced body weights, and levels of PPARγ and C/EBPα in fat tissues. Furthermore, insulin resistance was ameliorated by LFE treatment, with reduced adipose tissue inflammation and hepatic steatosis. Thus, LFE and FSB were found to act as PPARγ antagonists that improve insulin sensitivity and metabolic profiles. We propose that LFE and its active component FSB offer a new therapeutic strategy for metabolic disorders including obesity and insulin resistance.


Assuntos
Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , PPAR gama/antagonistas & inibidores , Primulaceae/química , Saponinas/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Proteínas de Transporte , Linhagem Celular , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , PPAR gama/química , PPAR gama/metabolismo , Ligação Proteica , Saponinas/química
16.
Bioorg Med Chem Lett ; 26(11): 2580-3, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27117431

RESUMO

p21-Activated kinases (PAKs) which belong to the family of ste20 serine/threonine protein kinases regulate cytoskeletal reorganization, cell motility, cell proliferation, and oncogenic transformation which are all related to the cellular functions during cancer induction and metastasis. The fact that PAK mutations are detected in multiple tumor tissues makes PAKs a novel therapeutic drug target. In this study, an imidazo[4,5-b]pyridine-based PAK4 inhibitor, KY-04045 (6-Bromo-2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), was discovered using a virtual site-directed fragment-based drug design and was validated using an inhibition assay. Although PAK4 affinity to KY-04045 seems much weaker than that of the reported PAK4 inhibitors, the location of KY-04045 is clearly defined in the structure of PAK4 co-crystallized with KY-04045. The crystal structure illustrates that the pyrazole and imidazopyridine rings of KY-04045 are sufficient for mediating PAK4 hinge loop interaction. Hence, we believe that KY-04045 can be exploited as a basic building block in designing novel imidazo[4,5-b]pyridine-based PAK4 inhibitors.


Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
17.
Bioorg Med Chem Lett ; 26(4): 1169-72, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26810261

RESUMO

To study the molecular action of ischemic Fas-mediated cell death inhibitor, we prepared fluorescent-tagged and biotin-tagged probes of the potent inhibitor, KR-33494, of ischemic cell death. We used the molecular modeling technique to find the proper position for attaching those probes with minimum interference in the binding process of probes with Fas-mediated cell death target, FAF1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Biotina/química , Desenho de Drogas , Corantes Fluorescentes/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína
18.
Bioorg Med Chem Lett ; 25(18): 3947-52, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26231159

RESUMO

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/ß leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound.


Assuntos
Desenho de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , TYK2 Quinase/metabolismo
19.
Int J Mol Sci ; 15(11): 20403-12, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25383681

RESUMO

We report the discovery of aurora kinase inhibitor using the fragment-based virtual screening by multi-docking strategy. Among a number of fragments collected from eMololecules, we found four fragment molecules showing potent activity (>50% at 100 µM) against aurora kinase. Based on the explored fragment scaffold, we selected two compounds in our synthesized library and validated the biological activity against Aurora kinase.


Assuntos
Aurora Quinases/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacologia , Interface Usuário-Computador , Ligantes , Relação Estrutura-Atividade
20.
Antiviral Res ; 107: 66-75, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24794525

RESUMO

A target-free approach was applied to discover anti-influenza viral compounds, where influenza infected Madin-Darby canine kidney cells were treated 7500 different small organic chemicals individually and reduction of virus-induced cytopathic effect was measured. One of the hit compounds was (Z)-1-((5-fluoro-1H-indol-3-yl)methylene)-6-methyl-4-thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-one (15a) with half-maximal effective concentrations of 17.4-21.1µM against influenza A/H1N1, A/H3N2 and B viruses without any cellular toxicity at 900µM. To investigate the structure-activity relationships, two dozens of the hit analogs were synthesized. Among them, 15g, 15j, 15q, 15s, 15t and 15x had anti-influenza viral activity comparable or superior to that of the initial hit. The anti-influenza viral compounds efficiently suppressed not only viral protein level of the infected cells but also production of viral progeny in the culture supernatants in a dose-dependent manner. Based on a mode-of-action study, they did not affect virus entry or RNA replication. Instead, they suppressed viral neuraminidase activity. This study is the first to demonstrate that dihydrofuropyridinones could serve as lead compounds for the discovery of alternative influenza virus inhibitors.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Piridonas/síntese química , Piridonas/farmacologia , Animais , Efeito Citopatogênico Viral , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/enzimologia , Orthomyxoviridae/fisiologia , Relação Estrutura-Atividade , Proteínas Virais/antagonistas & inibidores
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