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2.
Med Clin North Am ; 105(4): 627-641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059242

RESUMO

Psoriasis is a systemic inflammatory condition that negatively affects the quality of life and medical health of 125 million individuals globally. Although psoriasis has historically been viewed as a skin-limited disease and managed with topical agents (eg, coal tar, corticosteroids, and vitamin D analogues), the recontextualization of psoriasis as a systemic condition involving multiple organ systems has prompted the development of numerous immunomodulating, systemic agents with more targeted mechanisms of action. This article briefly discusses the indications and nuances of new and developing therapeutic agents for psoriasis management.


Assuntos
Interleucinas/antagonistas & inibidores , Psoríase/patologia , Psoríase/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Ensaios Clínicos como Assunto , Alcatrão/administração & dosagem , Alcatrão/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Psoríase/diagnóstico , Psoríase/psicologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida/psicologia , Receptores de Hidrocarboneto Arílico , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
3.
Food Funct ; 12(9): 3978-3991, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977989

RESUMO

Tyrosinase is considered a molecular marker of melanoma, and few natural antitumor drugs targeting tyrosinase have been identified. In this study, proanthocyanidins (PAs) were isolated from the leaves of Photinia × fraseri and their structures were characterized by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the effects of antityrosinase activity were investigated. The results showed that the basic structural units of PAs are composed of catechin and epicatechin and that oligomer is the main component. PAs exhibited better antityrosinase activity via chelation of copper ions and by disturbing o-quinone production. Furthermore, analyses of the cell cycle, apoptosis rate, and regulation of melanin protein expression revealed preliminarily that PAs could affect melanin production by downregulating microphthalmia transcription factor (MITF) expression and by inhibiting the activities of tyrosinase and tyrosinase related protein 1 (TRP-1), leading to cell cycle arrest and apoptosis of melanoma cells. Collectively, our study demonstrated that PAs are potential tyrosinase inhibitors and have good antimelanoma effects. These findings provide a theoretical support for the application of tyrosinase inhibitors and for further drug development.


Assuntos
Apoptose , Ciclo Celular/efeitos dos fármacos , Melanoma Experimental/patologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Photinia/química , Proantocianidinas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Levodopa/química , Levodopa/metabolismo , Melaninas/biossíntese , Melaninas/genética , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredução , Oxirredutases/genética , Oxirredutases/metabolismo , Ácido Periódico , Folhas de Planta/química , Proantocianidinas/química , Proantocianidinas/isolamento & purificação
4.
Science ; 372(6543): 716-721, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33986176

RESUMO

Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon's bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.


Assuntos
Eritropoese , Mitocôndrias/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética , Proteínas de Peixe-Zebra/metabolismo , Animais , Ciclo do Ácido Cítrico , Metilação de DNA , Transporte de Elétrons , Embrião não Mamífero/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Histonas/metabolismo , Leflunomida/farmacologia , Redes e Vias Metabólicas , Metilação , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Consumo de Oxigênio , Fatores de Transcrição/genética , Ubiquinona/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
5.
Anticancer Res ; 41(5): 2287-2296, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952454

RESUMO

BACKGROUND/AIM: Indoleamine 2,3-dioxygenase (IDO) is regarded as an important molecular target for cancer immune therapy. This study aimed to examine the IDO1 inhibitory activity of newly synthesized indomethacin derivatives to develop an IDO1 inhibitor. MATERIALS AND METHODS: The inhibitory effects of indole-containing compounds against recombinant human IDO1 (rhIDO1) were evaluated. RESULTS: While some drugs including those with an indole scaffold could inhibit rhIDO1, simple indole compounds were inactive. A total of 27 indomethacin derivatives, including 18 newly synthesized derivatives, were evaluated. Numerous derivatives showed enhanced IDO1 inhibitory activity. The functional group at the 3-position had a strong effect on IDO1 inhibitory activity. The IDO1 inhibitory activity was not directly correlated with tumor cell cytotoxicity. CONCLUSION: We report the finding of novel IDO1 inhibitors and the structure-activity relationship based on indomethacin derivatives. Our findings will be beneficial for the development of IDO1 inhibitors for cancer immune therapy.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indometacina/farmacologia , Relação Estrutura-Atividade , Biocatálise/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indometacina/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular
6.
J Enzyme Inhib Med Chem ; 36(1): 1016-1028, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33980119

RESUMO

Elastase is a proteolytic enzyme belonging to the family of hydrolases produced by human neutrophils, monocytes, macrophages, and endothelial cells. Human neutrophil elastase is known to play multiple roles in the human body, but an increase in its activity may cause a variety of diseases. Elastase inhibitors may prevent the development of psoriasis, chronic kidney disease, respiratory disorders (including COVID-19), immune disorders, and even cancers. Among polyphenolic compounds, some flavonoids and their derivatives, which are mostly found in herbal plants, have been revealed to influence elastase release and its action on human cells. This review focuses on elastase inhibitors that have been discovered from natural sources and are biochemically characterised as flavonoids. The inhibitory activity on elastase is a characteristic of flavonoid aglycones and their glycoside and methylated, acetylated and hydroxylated derivatives. The presented analysis of structure-activity relationship (SAR) enables the determination of the chemical groups responsible for evoking an inhibitory effect on elastase. Further study especially of the in vivo efficacy and safety of the described natural compounds is of interest in order to gain better understanding of their health-promoting potential.


Assuntos
Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Neutrófilos/enzimologia , /tratamento farmacológico , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Elastase de Leucócito/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neutrófilos/efeitos dos fármacos , Relação Estrutura-Atividade
7.
ChemistryOpen ; 10(5): 593-599, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34010501

RESUMO

Scientists all over the world are facing a challenging task of finding effective therapeutics for the coronavirus disease (COVID-19). One of the fastest ways of finding putative drug candidates is the use of computational drug discovery approaches. The purpose of the current study is to retrieve natural compounds that have obeyed to drug-like properties as potential inhibitors. Computational molecular modelling techniques were employed to discover compounds with potential SARS-CoV-2 inhibition properties. Accordingly, the InterBioScreen (IBS) database was obtained and was prepared by minimizing the compounds. To the resultant compounds, the absorption, distribution, metabolism, excretion and toxicity (ADMET) and Lipinski's Rule of Five was applied to yield drug-like compounds. The obtained compounds were subjected to molecular dynamics simulation studies to evaluate their stabilities. In the current article, we have employed the docking based virtual screening method using InterBioScreen (IBS) natural compound database yielding two compounds has potential hits. These compounds have demonstrated higher binding affinity scores than the reference compound together with good pharmacokinetic properties. Additionally, the identified hits have displayed stable interaction results inferred by molecular dynamics simulation results. Taken together, we advocate the use of two natural compounds, STOCK1N-71493 and STOCK1N-45683 as SARS-CoV-2 treatment regime.


Assuntos
Antivirais/metabolismo , Produtos Biológicos/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas não Estruturais Virais/metabolismo , Antivirais/farmacocinética , Produtos Biológicos/farmacocinética , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Software , Proteínas não Estruturais Virais/farmacocinética
8.
Nat Commun ; 12(1): 2607, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972549

RESUMO

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.


Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Células-Tronco/metabolismo , Idoso , Aminopiridinas/uso terapêutico , Proteínas Estimuladoras de Ligação a CCAAT/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Epigenômica , Evolução Molecular , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Família Multigênica , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Piridinas/uso terapêutico , RNA-Seq , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Célula Única , Triazinas/uso terapêutico , Proteínas ras/genética
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 258: 119843, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933941

RESUMO

Eugenol, a major component in clove has various biological activities. The current study focused to the binding potential of eugenol with Xanthine oxidase (XO) were evaluated using multi spectroscopic techniques and in silico docking studies. Xanthine oxidase, a superoxide generating enzyme, catalyses hypoxanthine and xanthine to uric acid. An excessive uric acid and superoxide anion radical in our body causes many serious clinical complications. The activity and the structural alterations can be a significant method to reduce this kind of risk factors. The results obtained from the fluorescence titration exhibited the interactions initiated by a static quenching mechanism. The ultraviolet (UV), fourier-transform infrared (FTIR), circular dichroism (CD) spectroscopic analysis of eugenol bind with XO indicated the secondary structural alteration in XO. Docking studies showed molecular level interaction of eugenol with the amino acid residues of Thr 1010, Phe 914, Phe 1009, Leu 1014, Phe 1009, Val 1011, Arg 880, Ala 1078, Glu 802, Leu 648and Leu 873 which residing at the catalytic active site of the XO. These results inferred that the eugenol can interact with XO in a remarkable manner and these findings provide a supporting data for the XO inhibition studies to propose a new lead compound.


Assuntos
Eugenol , Xantina Oxidase , Domínio Catalítico , Simulação por Computador , Inibidores Enzimáticos/farmacologia
10.
Nat Commun ; 12(1): 2475, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931637

RESUMO

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNß. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.


Assuntos
Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , Infecções por HIV/imunologia , HIV-1/metabolismo , Imidazóis/farmacologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antirretrovirais/farmacologia , Apoptose/genética , Azepinas/química , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/química , Inibidores Enzimáticos/farmacologia , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Imidazóis/química , Hibridização in Situ Fluorescente , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Células Jurkat , Simulação de Acoplamento Molecular , RNA Viral/metabolismo , Análise de Célula Única , Survivina/metabolismo , Ativação Viral/efeitos dos fármacos , Replicação Viral/genética
11.
Nat Commun ; 12(1): 2814, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990561

RESUMO

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.


Assuntos
Inibidores Enzimáticos/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Esterol O-Aciltransferase/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Humanos , /farmacologia , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/virologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Linfócitos T/imunologia
12.
Nat Commun ; 12(1): 2792, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990599

RESUMO

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Animais , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Domínio Catalítico/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Desenho de Fármacos , Descoberta de Drogas , Inibidores Enzimáticos/química , Feminino , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Proteína de Leucina Linfoide-Mieloide/genética , Oncogenes , Domínios Proteicos , Proteínas Recombinantes de Fusão/genética
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 259: 119910, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992895

RESUMO

Protein tyrosine phosphatase-1B (PTP1B) is a novel and indispensable drug target for the treatment of type 2 diabetes mellitus (T2DM). Procyanidins are flavonoids that exhibit a significant hypoglycemic function. However, the potential inhibitory effects of procyanidins on PTP1B are unclear. In this study, the interaction mechanisms of PTP1B with procyanidin B1 (PB1) and procyanidin B2 (PB2) were investigated through kinetics analysis, UV-visible spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy and molecular docking. The results showed that PB1 and PB2 could inhibit the activity of PTP1B in a mixed inhibition mode, which was one of the reversible inhibition types. Multi-spectral analysis showed that PB1/PB2 formed complexes with PTP1B, which effectively quenched the intrinsic fluorescence of PTP1B based on the static mechanism. The values of the binding constants were KS(PTP1B-PB1) = 4.06 × 102 L·mol-1 and KS(PTP1B-PB2) = 2.53 × 102 L·mol-1, indicating that the binding affinity of PTP1B to PB1 was higher than that for PB2. PB1 and PB2 both changed the secondary structure of the enzyme, thereby decreasing the PTP1B activity. Thermodynamic investigations revealed that the binding of procyanidin B1 and B2 to PTP1B was spontaneous in both cases, and highlighted the key role of hydrophobic interactions. Molecular docking analysis provided further information regarding the interactions between PB1 or PB2 and the amino acid residues of PTP1B. Moreover, PB1 and PB2 were found to down-regulate the expression level of PTP1B in insulin-resistant HepG2 cells. These findings are the first to elucidate the inhibitory effects of PB1 and PB2 on PTP1B, and highlight the role of procyanidins as dietary supplements in regulating T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Proantocianidinas , Biflavonoides , Catequina , Inibidores Enzimáticos , Humanos , Cinética , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Análise Espectral
14.
J Agric Food Chem ; 69(21): 5804-5817, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008970

RESUMO

A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 µM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight" pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 µg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.


Assuntos
Piruvato Desidrogenase (Lipoamida) , Complexo Piruvato Desidrogenase , Antifúngicos/farmacologia , Botrytis , Candida , Colletotrichum , Inibidores Enzimáticos , Escherichia coli , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas
15.
Sci Rep ; 11(1): 10290, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986405

RESUMO

As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.


Assuntos
Amidas/farmacologia , Carbamatos/farmacologia , Ciclopropanos/farmacologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Quinoxalinas/farmacologia , RNA Helicases/antagonistas & inibidores , Sulfonamidas/farmacologia , Triazóis/farmacologia , Antivirais/farmacologia , Reposicionamento de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Domínios Proteicos/efeitos dos fármacos , RNA Helicases/química , RNA Helicases/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
16.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946210

RESUMO

Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N4-hydroxy-dCMP (N4-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N4-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N4-OH-dCMP and N5,10-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N4-OH-dCMP and N5,10-methylenetetrahdrofolate. The crystal structure of the mouse TS-N4-OH-dCMP complex soaked with N5,10-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer.


Assuntos
Desoxicitidina Monofosfato/análogos & derivados , Inibidores Enzimáticos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Trichinella/enzimologia , Animais , Cristalografia por Raios X , Desoxicitidina Monofosfato/química , Desoxicitidina Monofosfato/farmacologia , Inibidores Enzimáticos/química , Humanos , Camundongos , Simulação de Acoplamento Molecular , Espectrofotometria , Timidilato Sintase/química , Timidilato Sintase/metabolismo , Triquinelose/parasitologia
17.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946573

RESUMO

The present study aimed to evaluate the effect of Jerusalem artichoke processing methods and drying methods (freeze drying, sublimation drying, vacuum drying) on the basic physicochemical parameters, profiles and contents of sugars and polyphenolic compounds, and health-promoting properties (antioxidant activity, inhibition of the activities of α-amylase, α-glucosidase, and pancreatic lipase) of the produced purée. A total of 25 polyphenolic compounds belonging to hydroxycinnamic phenolic acids (LC-PDA-MS-QTof) were detected in Jerusalem artichoke purée. Their average content in the raw material was at 820 mg/100 g dm (UPLC-PDA-FL) and was 2.7 times higher than in the cooked material. The chemical composition and the health-promoting value of the purées were affected by the drying method, with the most beneficial values of the evaluated parameters obtained upon freeze drying. Vacuum drying could offer an alternative to freeze drying, as both methods ensured relatively comparable values of the assessed parameters.


Assuntos
Fenômenos Químicos , Alimento Funcional/análise , Helianthus/química , Extratos Vegetais/química , Antioxidantes/química , Antioxidantes/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Polifenóis/química , Açúcares/química
18.
PLoS One ; 16(5): e0251801, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33984041

RESUMO

Drug repurposing studies targeting inhibition of RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have exhibited the potential effect of small molecules. In the present work a detailed interaction study between the phytochemicals from Indian medicinal plants and the RdRP of SARS-CoV-2 has been performed. The top four phytochemicals obtained through molecular docking were, swertiapuniside, cordifolide A, sitoindoside IX, and amarogentin belonging to Swertia chirayita, Tinospora cordifolia and Withania somnifera. These ligands bound to the RdRP were further studied using molecular dynamics simulations. The principal component analysis of these systems showed significant conformational changes in the finger and thumb subdomain of the RdRP. Hydrogen bonding, salt-bridge and water mediated interactions supported by MM-GBSA free energy of binding revealed strong binding of cordifolide A and sitoindoside IX to RdRP. The ligand-interacting residues belonged to either of the seven conserved motifs of the RdRP. These residues were polar and charged amino acids, namely, ARG 553, ARG 555, ASP 618, ASP 760, ASP 761, GLU 811, and SER 814. The glycosidic moieties of the phytochemicals were observed to form favourable interactions with these residues. Hence, these phytochemicals may hold the potential to act as RdRP inhibitors owing to their stability in binding to the druggable site.


Assuntos
/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Compostos Fitoquímicos/farmacologia , /enzimologia , Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , /metabolismo , /efeitos dos fármacos
19.
J Agric Food Chem ; 69(20): 5734-5745, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33999624

RESUMO

Exploring novel p-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors has become one of the most promising research directions in herbicide innovation. On the basis of our tremendous interest in exploiting more powerful HPPD inhibitors, we designed a family of benzyl-containing triketone-aminopyridines via a structure-based drug design (SBDD) strategy and then synthesized them. Among these prepared derivatives, the best active 3-hydroxy-2-(3,5,6-trichloro-4-((4-isopropylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one (23, IC50 = 0.047 µM) exhibited a 5.8-fold enhancement in inhibiting Arabidopsis thaliana (At) HPPD activity over that of commercial mesotrione (IC50 = 0.273 µM). The predicted docking models and calculated energy contributions of the key residues for small molecules suggested that an additional π-π stacking interaction with Phe-392 and hydrophobic contacts with Met-335 and Pro-384 were detected in AtHPPD upon the binding of the best active compound 23 compared with that of the reference mesotrione. Such a molecular mechanism and the resulting binding affinities coincide with the proposed design scheme and experimental values. It is noteworthy that inhibitors 16 (3-hydroxy-2-(3,5,6-trichloro-4-((4-chlorobenzyl)amino)picolinoyl)cyclohex-2-en-1-one), 22 (3-hydroxy-2-(3,5,6-trichloro-4-((4-methylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one), and 23 displayed excellent greenhouse herbicidal effects at 150 g of active ingredient (ai)/ha after postemergence treatment. Furthermore, compound 16 showed superior weed-controlling efficacy against Setaria viridis (S. viridis) versus that of the positive control mesotrione at multiple test dosages (120, 60, and 30 g ai/ha). These findings imply that compound 16, as a novel lead of HPPD inhibitors, possesses great potential for application in specifically combating the malignant weed S. viridis.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Herbicidas , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Aminopiridinas , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Ácidos Fenilpirúvicos , Plantas Daninhas/metabolismo , Relação Estrutura-Atividade
20.
Molecules ; 26(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916639

RESUMO

Valorization of vegetable oil waste residues is gaining importance due to their high protein and polyphenol contents. Protease inhibitors (PIs), proteins from these abundantly available waste residues, have recently gained importance in treating chronic diseases. This research aimed to use canola meal of genetically diverse Brassica napus genotypes, BLN-3347 and Rivette, to identify PIs with diverse functionalities in therapeutic and pharmacological applications. The canola meal PI purification steps involved: native PAGE and trypsin inhibition activity, followed by ammonium sulfate fractionation, anion exchange, gel filtration, and reverse-phase chromatography. The purified PI preparations were characterized using SDS-PAGE, isoelectric focusing (IEF), and N terminal sequencing. SDS-PAGE analysis of PI preparations under native reducing and nonreducing conditions revealed three polymorphic PIs in each genotype. The corresponding IEF of the genotype BLN-3347, exhibited three acidic isoforms with isoelectric points (pI) of 4.6, 4.0, and 3.9, while Rivette possessed three isoforms, exhibiting two basic forms of pI 8.65 and 9.9, and one acidic of pI 6.55. Purified PI preparations from both the genotypes displayed dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibition activities; the BLN-3347 PI preparation exhibited a strong inhibitory effect with lower IC50 values (DPP-IV 37.42 µg/mL; ACE 129 µg/mL) than that from Rivette (DPP-IV 67.97 µg/mL; ACE 376.2 µg/mL). In addition to potential human therapy, these highly polymorphic PIs, which can inhibit damaging serine proteases secreted by canola plant pathogens, have the potential to be used by canola plant breeders to seek qualitative trait locus (QTLs) linked to genes conferring resistance to canola diseases.


Assuntos
Anti-Hipertensivos/farmacologia , Brassica napus/química , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Peptidil Dipeptidase A/química , Sequência de Aminoácidos , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Brassica napus/genética , Brassica napus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Genótipo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Focalização Isoelétrica , Cinética , Extração Líquido-Líquido/métodos , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/química
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