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1.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204232

RESUMO

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC50 values of 24.3 ± 0.8, and 47.7 ± 1.1 µM) and α-glucosidase (IC50 values of 92.1 ± 0.8, and 167.4 ± 0.4 µM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure-activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.


Assuntos
Evodia/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade , alfa-Glucosidases/efeitos dos fármacos , alfa-Glucosidases/metabolismo
2.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207301

RESUMO

The regioselective synthesis of novel functionalized condensed organochalcogen compounds by chalcogenocyclofunctionalization reactions based on chalcogen halides and the natural products thymol and carvacrol has been developed. The reactions of selenium dibromide with allyl thymol and allyl carvacrol proceeded in methylene chloride at room temperature in the presence of NaHCO3 affording bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenides in 90-92% yield. Similar sulfides were obtained in 70-72% yields by the reaction of sulfur dichloride in chloroform under reflux. Trihalotellanes containing the same organic moieties were synthesized from allyl thymol, allyl carvacrol and tellurium tetrachloride or tetrabromide in quantitative yields. Corresponding functionalized ditellurides were prepared in 91-92% yields by the reduction of the trichlorotellanes with sodium metabisulfite in two-phase solvent system. The comparison of reactivity of sulfur, selenium and tellurium halides in chalcogenocyclofunctionalization and distinguishing features of each reaction were discussed.


Assuntos
Produtos Biológicos/química , Calcogênios/química , Cimenos/química , Selênio/química , Enxofre/química , Telúrio/química , Timol/química
3.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208597

RESUMO

Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant Staphylococcus aureus (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious and time-consuming process of conducting the necessary preclinical tests on these compounds. In this study, cheminformatic profiling was performed on 111 anti-MRSA NPs (AMNPs), using a few orally administered conventional drugs for MRSA (CDs) as reference, to identify compounds with prospects to become drug candidates. This was followed by prioritizing these hits and identifying the liabilities among the AMNPs for possible optimization. Cheminformatic profiling revealed that most of the AMNPs were within the required drug-like region of the investigated properties. For example, more than 76% of the AMNPs showed compliance with the Lipinski, Veber, and Egan predictive rules for oral absorption and permeability. About 34% of the AMNPs showed the prospect to penetrate the blood-brain barrier (BBB), an advantage over the CDs, which are generally non-permeant of BBB. The analysis of toxicity revealed that 59% of the AMNPs might have negligible or no toxicity risks. Structure-activity relationship (SAR) analysis revealed chemical groups that may be determinants of the reported bioactivity of the compounds. A hit prioritization strategy using a novel "desirability scoring function" was able to identify AMNPs with the desired drug-likeness. Hit optimization strategies implemented on AMNPs with poor desirability scores led to the design of two compounds with improved desirability scores.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Quimioinformática/métodos , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos/métodos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
4.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199336

RESUMO

The natural compound ravenelin was isolated from the biomass extracts of Exserohilum rostratum fungus, and its antimicrobial, antiplasmodial, and trypanocidal activities were evaluated. Ravenelin was isolated by column chromatography and HPLC and identified by NMR and MS. The susceptibility of Gram-positive and Gram-negative bacteria strains to ravenelin was determined by microbroth dilution assay. Cytotoxicity was evaluated in hepatocarcinoma cells (HepG2) and BALB/c peritoneal macrophages by using MTT. SYBR Green I-based assay was used in the asexual stages of Plasmodium falciparum. Trypanocidal activity was tested against the epimastigote and intracellular amastigote forms of Trypanosoma cruzi. Ravenelin was active against Gram-positive bacteria strains, with emphasis on Bacillus subtilis (MIC value of 7.5 µM). Ravenelin's antiparasitic activities were assessed against both the epimastigote (IC50 value of 5 ± 1 µM) and the intracellular amastigote forms of T. cruzi (IC50 value of 9 ± 2 µM), as well as against P. falciparum (IC50 value of 3.4 ± 0.4 µM). Ravenelin showed low cytotoxic effects on both HepG2 (CC50 > 50 µM) and peritoneal macrophage (CC50 = 185 ± 1 µM) cells with attractive selectivity for the parasites (SI values > 15). These findings indicate that ravenelin is a natural compound with both antibacterial and antiparasitic activities, and considerable selectivity indexes. Therefore, ravenelin is an attractive candidate for hit-to-lead development.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Ascomicetos/química , Macrófagos Peritoneais/citologia , Xantonas/farmacologia , Animais , Antibacterianos/química , Antiprotozoários/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Biomassa , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Xantonas/química
5.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199433

RESUMO

Gelam honey (GH) is a prized natural product synthesized from the nectar of flowers from Gelam trees (Melaleuca sp.). Gelam is an evergreen tree species that grows in tropical regions such as Malaysia. GH is a multifloral honey with proven antioxidant and anti-inflammatory properties. However, the beneficial effect of GH on female reproductive tissue has yet to be substantiated. Herein, we investigated the effects of GH administration on the uterine and vaginal epithelial thickness of sexually mature Sprague-Dawley rats. Epithelia thickness could be an indicator of an atrophy manifesting as a symptom of a cardio syndrome. Rats were given oral doses of GH in four groups for 14 days; the lowest dose was 0.2 g GH/kg body weight (bw) rat/day and the highest dose was 8 g GH/kg bw rat/day. The physicochemical characteristics of GH were assessed through hydroxymethylfurfural and moisture content determination and sugar identification. GH attenuated the atrophy of the uterine and vaginal epithelia and increased the thickness of the endometrial stroma and endometrial surface endothelial layer. However, the dissonance observed in the effect of GH administration on the vaginal epithelium requires further investigation. Nevertheless, GH may have a strong potential in attenuating uterine and vaginal atrophies.


Assuntos
Produtos Biológicos/administração & dosagem , Mel/análise , Melaleuca/química , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Atrofia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Feminino , Néctar de Plantas/química , Ratos , Ratos Sprague-Dawley , Útero/patologia , Vagina/patologia
6.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206588

RESUMO

Anthocyanins are natural products that give color to plants. As natural plant pigments, anthocyanins also have a series of health-promoting benefits. Many researchers have proved that anthocyanins have therapeutic effects on diseases, such as circulatory, nervous, endocrine, digestive, sensory, urinary and immune systems. Additionally, a large number of studies have reported that anthocyanins have an anticancer effect through a wide range of anti-inflammatory and antioxidant effects. The anti-disease impact and mechanism of anthocyanins are diverse, so they have high research value. This review summarizes the research progress of anthocyanins on the pharmacological agents of different diseases to provide references for subsequent research.


Assuntos
Antocianinas , Anti-Inflamatórios , Antioxidantes , Produtos Biológicos , Plantas/química , Antocianinas/química , Antocianinas/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Humanos
7.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205539

RESUMO

This review outlines methods to investigate the structure of natural products with emphasis on intramolecular hydrogen bonding, tautomerism and ionic structures using NMR techniques. The focus is on 1H chemical shifts, isotope effects on chemical shifts and diffusion ordered spectroscopy. In addition, density functional theory calculations are performed to support NMR results. The review demonstrates how hydrogen bonding may lead to specific structures and how chemical equilibria, as well as tautomeric equilibria and ionic structures, can be detected. All these features are important for biological activity and a prerequisite for correct docking experiments and future use as drugs.


Assuntos
Produtos Biológicos/química , Preparações Farmacêuticas/química , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular/métodos
8.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205746

RESUMO

This work addressed the preservative behaviour of different icing media containing extracts from the alga Bifurcaria bifurcata. A comparative study of the antimicrobial and antioxidant effects of aqueous and ethanolic extracts of this macroalga was carried out. Whole hake (Merluccius merluccius) pieces were stored in ice containing either kind of extract and analysed for quality changes throughout a 13-day storage period. A progressive loss of microbial and biochemical quality was detected in all batches as chilling time increased. A significant inhibitory effect (p < 0.05) on microbial activity could be observed as a result of including the aqueous (lowering of psychrotrophic and lipolytic counts and pH value) and ethanolic (lowering of psychrotrophic and lipolytic counts) extracts. Additionally, both kinds of extract led to a substantial inhibition (p < 0.05) in the lipid hydrolysis rate (formation of free fatty acids), greater in the case of the batch containing ethanolic extract. Concerning lipid oxidation, a similar inhibitory effect (p < 0.05) on the formation of secondary compounds (thiobarbituric acid substances) was noticed in fish specimens corresponding to both alga extracts; however, more (p < 0.05) peroxide formation was detected in fish corresponding to the ethanolic extract batch. A preservative effect can be concluded for both kinds of extract; this effect agrees with previous studies reporting the presence of hydrophilic and lipophilic bioactive compounds in B. bifurcata.


Assuntos
Produtos Biológicos/farmacologia , Conservantes de Alimentos/farmacologia , Feófitas/efeitos dos fármacos , Alga Marinha/química , Animais , Antioxidantes/farmacologia , Produtos Biológicos/química , Etanol/química , Peixes , Conservação de Alimentos/métodos , Gadiformes , Oxirredução/efeitos dos fármacos , Alimentos Marinhos , Água/química
9.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205768

RESUMO

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proteases 3C de Coronavírus/química , Poríferos/química , Poríferos/metabolismo , RNA Polimerase Dependente de RNA/química , SARS-CoV-2/efeitos dos fármacos , Amino Açúcares/química , Amino Açúcares/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacocinética , COVID-19/tratamento farmacológico , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Piridinas/química , Piridinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/metabolismo
10.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200887

RESUMO

Royal jelly is a natural substance produced by worker bees that possesses a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and protective. Although fresh royal jelly is kept at low temperatures, to increase its stability, it needs to be incorporated into pharmaceutical formulations, such as in situ gels. The aim of this study was to formulate in situ ocular gels containing Lithuanian royal jelly for topical corneal use in order to increase the retention time of the formulation on the ocular surface and bioavailability. Gels were evaluated for physicochemical characteristics (pH, rheological properties, refractive index) and in vitro drug release measuring the amount of 10-hydroxy-2-decenoic acid (10-HDA). An ocular irritation test and cell viability tests were performed using the SIRC (Statens Seruminstitut Rabbit Cornea) cell culture line. Results indicated that all the in situ gels were within an acceptable pH and refractive index range close to corneal properties. Rheology studies have shown that the gelation temperature varies between 25 and 32 °C, depending on the amount of poloxamers. The release studies have shown that the release of 10-HDA from in situ gels is more sustained than royal jelly suspension. All gel formulations were non-irritant according to the short-time exposure test (STE) using the SIRC cell culture line, and long-term cell viability studies indicated that the formulations used in small concentrations did not induce cell death. Prepared in situ gels containing royal jelly have potential for ocular drug delivery, and they may improve the bioavailability, stability of royal jelly, and formation of non-irritant ocular formulations.


Assuntos
Córnea/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Géis/química , Géis/farmacologia , Animais , Abelhas/metabolismo , Disponibilidade Biológica , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Córnea/metabolismo , Ácidos Decanoicos/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Géis/farmacocinética , Poloxâmero/química , Coelhos , Reologia , Temperatura
11.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200973

RESUMO

Nucleocapsid proteins (NCp) are zinc finger (ZF) proteins, and they play a central role in HIV virus replication, mainly by interacting with nucleic acids. Therefore, they are potential targets for anti-HIV therapy. Natural products have been shown to be able to inhibit HIV, such as turmeric and licorice, which is widely used in traditional Chinese medicine. Liquiritin (LQ), isoliquiritin (ILQ), glycyrrhizic acid (GL), glycyrrhetinic acid (GA) and curcumin (CUR), which were the major active components, were herein chosen to study their interactions with HIV-NCp7 C-terminal zinc finger, aiming to find the potential active compounds and reveal the mechanism involved. The stacking interaction between NCp7 tryptophan and natural compounds was evaluated by fluorescence. To elucidate the binding mode, mass spectrometry was used to characterize the reaction mixture between zinc finger proteins and active compounds. Subsequently, circular dichroism (CD) spectroscopy and molecular docking were used to validate and reveal the binding mode from a structural perspective. The results showed that ILQ has the strongest binding ability among the tested compounds, followed by curcumin, and the interaction between ILQ and the NCp7 zinc finger peptide was mediated by a noncovalent interaction. This study provided a scientific basis for the antiviral activity of turmeric and licorice.


Assuntos
Fármacos Anti-HIV/farmacologia , Produtos Biológicos/farmacologia , Curcuma/química , Glycyrrhiza/química , HIV-1/efeitos dos fármacos , Dedos de Zinco/efeitos dos fármacos , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Produtos Biológicos/química , Proteínas do Capsídeo/metabolismo , HIV-1/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Replicação Viral/efeitos dos fármacos
12.
Biomed Res Int ; 2021: 6696012, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124259

RESUMO

A global pandemic has emerged following the appearance of the new severe acute respiratory virus whose official name is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strongly affecting the health sector as well as the world economy. Indeed, following the emergence of this new virus, despite the existence of a few approved and known effective vaccines at the time of writing this original study, a sense of urgency has emerged worldwide to discover new technical tools and new drugs as soon as possible. In this context, many studies and researches are currently underway to develop new tools and therapies against SARS CoV-2 and other viruses, using different approaches. The 3-chymotrypsin (3CL) protease, which is directly involved in the cotranslational and posttranslational modifications of viral polyproteins essential for the existence and replication of the virus in the host, is one of the coronavirus target proteins that has been the subject of these extensive studies. Currently, the majority of these studies are aimed at repurposing already known and clinically approved drugs against this new virus, but this approach is not really successful. Recently, different studies have successfully demonstrated the effectiveness of artificial intelligence-based techniques to understand existing chemical spaces and generate new small molecules that are both effective and efficient. In this framework and for our study, we combined a generative recurrent neural network model with transfer learning methods and active learning-based algorithms to design novel small molecules capable of effectively inhibiting the 3CL protease in human cells. We then analyze these small molecules to find the correct binding site that matches the structure of the 3CL protease of our target virus as well as other analyses performed in this study. Based on these screening results, some molecules have achieved a good binding score close to -18 kcal/mol, which we can consider as good potential candidates for further synthesis and testing against SARS-CoV-2.


Assuntos
Antivirais/química , Produtos Biológicos/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Redes Neurais de Computação , Inibidores de Proteases/química , SARS-CoV-2/química , Bibliotecas de Moléculas Pequenas/química , Antivirais/classificação , Antivirais/farmacologia , Produtos Biológicos/classificação , Produtos Biológicos/farmacologia , COVID-19/tratamento farmacológico , Domínio Catalítico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Desenho de Fármacos , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Inibidores de Proteases/classificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/classificação , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato , Termodinâmica
13.
Biomed Res Int ; 2021: 6696012, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1255651

RESUMO

A global pandemic has emerged following the appearance of the new severe acute respiratory virus whose official name is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strongly affecting the health sector as well as the world economy. Indeed, following the emergence of this new virus, despite the existence of a few approved and known effective vaccines at the time of writing this original study, a sense of urgency has emerged worldwide to discover new technical tools and new drugs as soon as possible. In this context, many studies and researches are currently underway to develop new tools and therapies against SARS CoV-2 and other viruses, using different approaches. The 3-chymotrypsin (3CL) protease, which is directly involved in the cotranslational and posttranslational modifications of viral polyproteins essential for the existence and replication of the virus in the host, is one of the coronavirus target proteins that has been the subject of these extensive studies. Currently, the majority of these studies are aimed at repurposing already known and clinically approved drugs against this new virus, but this approach is not really successful. Recently, different studies have successfully demonstrated the effectiveness of artificial intelligence-based techniques to understand existing chemical spaces and generate new small molecules that are both effective and efficient. In this framework and for our study, we combined a generative recurrent neural network model with transfer learning methods and active learning-based algorithms to design novel small molecules capable of effectively inhibiting the 3CL protease in human cells. We then analyze these small molecules to find the correct binding site that matches the structure of the 3CL protease of our target virus as well as other analyses performed in this study. Based on these screening results, some molecules have achieved a good binding score close to -18 kcal/mol, which we can consider as good potential candidates for further synthesis and testing against SARS-CoV-2.


Assuntos
Antivirais/química , Produtos Biológicos/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Redes Neurais de Computação , Inibidores de Proteases/química , SARS-CoV-2/química , Bibliotecas de Moléculas Pequenas/química , Antivirais/classificação , Antivirais/farmacologia , Produtos Biológicos/classificação , Produtos Biológicos/farmacologia , COVID-19/tratamento farmacológico , Domínio Catalítico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Desenho de Fármacos , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Inibidores de Proteases/classificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/classificação , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato , Termodinâmica
14.
Food Chem ; 362: 130237, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091163

RESUMO

Thrombin is a key therapeutic target protein of thrombosis. To date, massive studies have focused on the exploration of antithrombotic compounds. Here we capitalize on molecular docking, molecular simulations and spectroscopic experiments for virtually screening natural products that can inhibit thrombin and elucidating their interaction mechanism. Six compounds are screened from a natural product database by a cross-analysis based on two semi-flexible molecular docking methods. We show that four compounds can effectively inhibit thrombin and Calceolarioside B is the most competitive one based on enzyme inhibition experiments. Moreover, the binding free energies of these compounds with thrombin exhibit a consistent rank trend with their enzyme inhibition assay results. In addition, the Van der Waals is the main force to drive the interaction between the ligands and the receptor, which can be deduced from the fluorescence spectral results. This work provides a new insight into the development of antithrombotic natural compounds.


Assuntos
Ingredientes de Alimentos/análise , Alimento Funcional/análise , Produtos Biológicos/química , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Trombina/metabolismo , Interface Usuário-Computador
15.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34156395

RESUMO

Heparanase (Hpse) is an endo-ß-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.


Assuntos
Produtos Biológicos/química , Glucuronidase/genética , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Produtos Biológicos/uso terapêutico , Glucuronidase/efeitos dos fármacos , Glucuronidase/ultraestrutura , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/genética , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Ligação Proteica/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade
16.
J Chromatogr A ; 1651: 462305, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34147833

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to play an important role in the immune escape process of tumors, and therefore is considered as a promising target for tumor immunotherapy. In this study, off-line and on-line capillary electrophoresis methods were developed for IDO1 inhibitors screening from natural product extracts. The optimized separation conditions of CE were achieved with 32 mM sodium tetraborate (pH 9.22) as background electrolyte, using a separation voltage of 21 kV. The off-line CE method was verified by the determination of enzymatic kinetic parameters and inhibitory mechanisms of two known inhibitors. A partial filling on-line CE method combined with rapid polarity switching was used for rapid screening of IDO1 inhibitors. The whole reaction and separation process was completed within 5 min. The on-line CE screening results showed that six of 18 natural products had inhibitory effect on IDO1, namely Carthamus tinctorius, Schisandra chinensis, Raisin, Coffee, Hawthorn and Radix angelicae sinensis. The results of on-line CE experiments were consistent with the off-line results, which proved the practicability and effectiveness of the method for inhibitors screening.


Assuntos
Técnicas de Química Analítica/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Eletroforese Capilar , Inibidores Enzimáticos/isolamento & purificação , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Produtos Biológicos/química , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos
17.
Nat Commun ; 12(1): 3864, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162873

RESUMO

Genetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Genoma Bacteriano/genética , Genoma de Planta/genética , Genômica/métodos , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Descoberta de Drogas/métodos , Estrutura Molecular , Metabolismo Secundário/genética
18.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073709

RESUMO

Polyphenols are natural organic compounds produced by plants, acting as antioxidants by reacting with ROS. These compounds are widely consumed in daily diet and many studies report several benefits to human health thanks to their bioavailability in humans. However, the digestion process of phenolic compounds is still not completely clear. Moreover, bioavailability is dependent on the metabolic phase of these compounds. The LogP value can be managed as a simplified measure of the lipophilicity of a substance ingested within the human body, which affects resultant absorption. The biopharmaceutical classification system (BCS), a method used to classify drugs intended for gastrointestinal absorption, correlates the solubility and permeability of the drug with both the rate and extent of oral absorption. BCS may be helpful to measure the bioactive constituents of foods, such as polyphenols, in order to understand their nutraceutical potential. There are many literature studies that focus on permeability, absorption, and bioavailability of polyphenols and their resultant metabolic byproducts, but there is still confusion about their respective LogP values and BCS classification. This review will provide an overview of the information regarding 10 dietarypolyphenols (ferulic acid, chlorogenic acid, rutin, quercetin, apigenin, cirsimaritin, daidzein, resveratrol, ellagic acid, and curcumin) and their association with the BCS classification.


Assuntos
Produtos Biológicos/metabolismo , Polifenóis/metabolismo , Animais , Disponibilidade Biológica , Produtos Biológicos/química , Produtos Biológicos/classificação , Produtos Biológicos/farmacocinética , Ácidos Cumáricos , Flavonas , Flavonóis , Humanos , Absorção Intestinal , Isoflavonas , Permeabilidade , Polifenóis/química , Polifenóis/classificação , Polifenóis/farmacocinética , Solubilidade , Estilbenos , Taninos
19.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072216

RESUMO

Cheonggukjang (CGJ, fermented soybean paste), a traditional Korean fermented dish, has recently emerged as a functional food that improves blood circulation and intestinal regulation. Considering that excessive consumption of refined salt is associated with increased incidence of gastric cancer, high blood pressure, and stroke in Koreans, consuming CGJ may be desirable, as it can be made without salt, unlike other pastes. Soybeans in CGJ are fermented by Bacillus strains (B. subtilis or B. licheniformis), Lactobacillus spp., Leuconostoc spp., and Enterococcus faecium, which weaken the activity of putrefactive bacteria in the intestines, act as antibacterial agents against pathogens, and facilitate the excretion of harmful substances. Studies on CGJ have either focused on improving product quality or evaluating the bioactive substances contained in CGJ. The fermentation process of CGJ results in the production of enzymes and various physiologically active substances that are not found in raw soybeans, including dietary fiber, phospholipids, isoflavones (e.g., genistein and daidzein), phenolic acids, saponins, trypsin inhibitors, and phytic acids. These components prevent atherosclerosis, oxidative stress-mediated heart disease and inflammation, obesity, diabetes, senile dementia, cancer (e.g., breast and lung), and osteoporosis. They have also been shown to have thrombolytic, blood pressure-lowering, lipid-lowering, antimutagenic, immunostimulatory, anti-allergic, antibacterial, anti-atopic dermatitis, anti-androgenetic alopecia, and anti-asthmatic activities, as well as skin improvement properties. In this review, we examined the physiological activities of CGJ and confirmed its potential as a functional food.


Assuntos
Produtos Biológicos , Fermentação , Alimento Funcional , Soja , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ingredientes de Alimentos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Estrutura Molecular , Avaliação Nutricional , Osteogênese/efeitos dos fármacos , Probióticos , Soja/química , Soja/metabolismo , Soja/microbiologia
20.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063095

RESUMO

The higher-order structure (HOS) of protein therapeutics is directly related to the function and represents a critical quality attribute. Currently, the HOS of protein therapeutics is characterized by methods with low to medium structural resolution, such as Fourier transform infrared (FTIR), circular dichroism (CD), intrinsic fluorescence spectroscopy (FLD), and differential scanning calorimetry (DSC). High-resolution nuclear magnetic resonance (NMR) methods have now been introduced, representing powerful approaches for HOS characterization (HOS by NMR). NMR is a multi-attribute method with unique abilities to give information on all structural levels of proteins in solution. In this study, we have compared 2D 1H-13C HSQC NMR with two established biophysical methods, i.e., near-ultraviolet circular dichroism (NUV-CD) and intrinsic fluorescence spectroscopy, for the HOS assessments for the folded and unfolded states of two monoclonal antibodies belonging to the subclasses IgG1 and IgG2. The study shows that the methyl region of the 1H-13C HSQC NMR spectrum is sensitive to both the secondary and tertiary structure of proteins and therefore represents a powerful tool in assessing the overall higher-order structural integrity of biopharmaceutical molecules.


Assuntos
Produtos Biológicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectroscopia de Prótons por Ressonância Magnética , Dicroísmo Circular , Imunoglobulina G/química , Dobramento de Proteína
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