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1.
Nihon Yakurigaku Zasshi ; 154(3): 143-150, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527365

RESUMO

Quantitative systems pharmacology (QSP) is an emerging field of modeling technologies that describes the dynamic interaction between biological systems and drugs. Recently, QSP is increasingly being applied to pharmaceutical drug discovery and development, and used for various types of decision makings. In contrast to empirical and statistical models, QSP represents complex systems of human physiology by integrating comprehensive biological information, hence, it can address various purposes including target and/or disease-related biomarker identification, hypothesis testing, and prediction of clinical efficacy or toxicity. On the other hand, structures of QSP models become quite complicated with huge amount of biological components, therefore, close collaboration between pharmacologists having profound knowledge of biology and drug metabolism and pharmacokinetics (DMPK) scientists, experts of model building, is crucial for QSP development and implementation. This article introduces, from DMPK scientists to pharmacologists, main features of QSP and its applications in pharmaceutical industries, and discusses challenges and future perspectives for effective utilization in drug discovery and development.


Assuntos
Descoberta de Drogas/métodos , Modelos Biológicos , Farmacologia/métodos , Humanos , Farmacocinética , Projetos de Pesquisa
2.
Expert Opin Ther Pat ; 29(9): 689-702, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402706

RESUMO

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs. Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes. Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Antígenos CD/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Desenho de Drogas , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Patentes como Assunto , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptor de Insulina/metabolismo
4.
Chem Commun (Camb) ; 55(69): 10192-10213, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31411602

RESUMO

Light is unsurpassed in its ability to modulate biological interactions. Since their discovery, chemists have been fascinated by photosensitive molecules capable of switching between isomeric forms, known as photoswitches. Photoswitchable peptides have been recognized for many years; however, their functional implementation in biological systems has only recently been achieved. Peptides are now acknowledged as excellent protein-protein interaction modulators and have been important in the emergence of photopharmacology. In this review, we briefly explain the different classes of photoswitches and summarize structural studies when they are incorporated into peptides. Importantly, we provide a detailed overview of the rapidly increasing number of examples, where biological modulation is driven by the structural changes. Furthermore, we discuss some of the remaining challenges faced in this field. These exciting proof-of-principle studies highlight the tremendous potential of photocontrollable peptides as optochemical tools for chemical biology and biomedicine.


Assuntos
Descoberta de Drogas , Peptídeos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Morte Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Isomerismo , Luz , Modelos Moleculares , Ácidos Nucleicos/metabolismo , Peptídeos/metabolismo , Processos Fotoquímicos , Mapas de Interação de Proteínas/efeitos dos fármacos
5.
J Enzyme Inhib Med Chem ; 34(1): 1373-1379, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347933

RESUMO

Butyrylcholinesterase (BChE) plays an important role in the progression of the Alzheimer's disease. In this study, we used a structure-based virtual screening (VS) approach to discover new BChE inhibitors. A ligand database was filtered and docked to the BChE protein using Glide program. The outcome from VS was filtered and the top ranked hits were thoroughly examined for their fitting into the protein active site. Consequently, the best 38 hits were selected for in vitro testing using Ellman's method, and six of which showed inhibition activity for BChE. Interestingly, the most potent hit (Compound 4) exhibited inhibitory activity against the BChE enzyme in the low micromolar level with an IC50 value of 8.3 µM. Hits obtained from this work can act as a starting point for future SAR studies to discover new BChE inhibitors as anti-Alzheimer agents.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/química , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
6.
BMC Bioinformatics ; 20(1): 378, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286864

RESUMO

BACKGROUND: The QuantiGene® Plex 2.0 platform (ThermoFisher Scientific) combines bDNA with the Luminex/xMAP magnetic bead capturing technology to assess differential gene expression in a compound exposure setting. This technology allows multiplexing in a single well of a 96 or 384 multi-well plate and can thus be used in high throughput drug discovery mode. Data interpretation follows a three-step normalization/transformation flow in which raw median fluorescent gene signals are transformed to fold change values with the use of proper housekeeping genes and negative controls. Clear instructions on how to assess the data quality and tools to perform this analysis in high throughput mode are, however, currently lacking. RESULTS: In this paper we introduce QGprofiler, an open source R based shiny application. QGprofiler allows for proper QuantiGene® Plex 2.0 assay optimization, choice of housekeeping genes and data pre-processing up to fold change, including appropriate QC metrics. In addition, QGprofiler allows for an Akaike information criterion based dose response fold change model selection and has a built-in tool to detect the cytotoxic potential of compounds evaluated in a high throughput screening campaign. CONCLUSION: QGprofiler is a user friendly, open source available R based shiny application, which is developed to support drug discovery campaigns. In this context, entire compound libraries/series can be tested in dose response against a gene signature of choice in search for new disease relevant chemical entities. QGprofiler is available at: https://qgprofiler.openanalytics.eu/app/QGprofiler.


Assuntos
Descoberta de Drogas/métodos , Perfilação da Expressão Gênica/métodos , Software
7.
J Enzyme Inhib Med Chem ; 34(1): 1218-1225, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286785

RESUMO

WaterLOGSY is a sensitive ligand-observed NMR experiment for detection of interaction between a ligand and a protein and is now well-established as a screening technique for fragment-based lead discovery. Here we develop and assess a protocol to derive ligand epitope mapping from WaterLOGSY data and demonstrate its general applicability in studies of fragment-sized ligands binding to six different proteins (glycogen phosphorylase, protein peroxiredoxin 5, Bcl-xL, Mcl-1, HSP90, and human serum albumin). We compare the WaterLOGSY results to those obtained from the more widely used saturation transfer difference experiments and to the 3D structures of the complexes when available. In addition, we evaluate the impact of ligand labile protons on the WaterLOGSY data. Our results demonstrate that the WaterLOGSY experiment can be used as an additional confirmation of the binding mode of a ligand to a protein.


Assuntos
Descoberta de Drogas/métodos , Espectroscopia de Ressonância Magnética/métodos , Sítios de Ligação , Proteínas/química
8.
Nature ; 571(7763): 72-78, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217586

RESUMO

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100-150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical-genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.


Assuntos
Antituberculosos/classificação , Antituberculosos/isolamento & purificação , Descoberta de Drogas/métodos , Deleção de Genes , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Antituberculosos/farmacologia , DNA Girase/metabolismo , Resistência Microbiana a Medicamentos , Ácido Fólico/biossíntese , Terapia de Alvo Molecular , Mycobacterium tuberculosis/citologia , Mycobacterium tuberculosis/enzimologia , Ácidos Micólicos/metabolismo , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/classificação , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Especificidade por Substrato , Inibidores da Topoisomerase II/isolamento & purificação , Inibidores da Topoisomerase II/farmacologia , Triptofano/biossíntese , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
9.
Nat Commun ; 10(1): 2745, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227705

RESUMO

Small molecule probes are indispensable tools to explore diverse cellular events. However, finding a specific probe of a target remains a high challenge. Here we report the discovery of Fast-TRFS, a specific and superfast fluorogenic probe of mammalian thioredoxin reductase, a ubiquitous enzyme involved in regulation of diverse cellular redox signaling pathways. By systematically examining the processes of fluorophore release and reduction of cyclic disulfides/diselenides by the enzyme, structural factors that determine the response rate and specificity of the probe are disclosed. Mechanistic studies reveal that the fluorescence signal is switched on by a simple reduction of the disulfide bond within the probe, which is in stark contrast to the sensing mechanism of published probes. The favorable properties of Fast-TRFS enable development of a high-throughput screening assay to discover inhibitors of thioredoxin reductase by using crude tissue extracts as a source of the enzyme.


Assuntos
Descoberta de Drogas/métodos , Corantes Fluorescentes/química , Imagem Molecular/métodos , Sondas Moleculares/química , Tiorredoxina Redutase 1/metabolismo , Animais , Produtos Biológicos/farmacologia , Misturas Complexas , Dissulfetos/química , Corantes Fluorescentes/metabolismo , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia Intravital/métodos , Microscopia de Fluorescência/métodos , Sondas Moleculares/metabolismo , Oxirredução , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Redutase 1/genética
10.
Expert Opin Drug Metab Toxicol ; 15(7): 595-612, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31174439

RESUMO

Introduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination.


Assuntos
Antiprotozoários/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Descoberta de Drogas/métodos , Resistência a Medicamentos , Humanos , Leishmaniose/parasitologia
11.
Top Curr Chem (Cham) ; 377(4): 19, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165274

RESUMO

This review is an effort to summarize recent developments in synthesis of O-glycosides and N-, C-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O-glycosides used in the treatment of diabetes are presented, followed by the N-glycosides and finally the C-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C-Glycosyl compounds mimicking O-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C-glycosides. Also N-glycosides such as N-(ß-D-glucopyranosyl)-amides, N-(ß-D-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5. In Sect. 6, biological mechanisms of action of the glycosides and patents of marketed drugs are described.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas/métodos , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Relação Estrutura-Atividade
13.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052253

RESUMO

In this paper we review the current status of high-performance computing applications in the general area of drug discovery. We provide an introduction to the methodologies applied at atomic and molecular scales, followed by three specific examples of implementation of these tools. The first example describes in silico modeling of the adsorption of small molecules to organic and inorganic surfaces, which may be applied to drug delivery issues. The second example involves DNA translocation through nanopores with major significance to DNA sequencing efforts. The final example offers an overview of computer-aided drug design, with some illustrative examples of its usefulness.


Assuntos
Descoberta de Drogas , Modelos Moleculares , Algoritmos , Projeto Auxiliado por Computador , Desenho de Drogas , Descoberta de Drogas/métodos , Genômica/métodos , Modelos Teóricos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nanoporos , Compostos Orgânicos/química , Análise de Sequência de DNA , Relação Estrutura-Atividade
14.
Molecules ; 24(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052598

RESUMO

BACKGROUND: Identifying possible drug-target interactions (DTIs) has become an important task in drug research and development. Although high-throughput screening is becoming available, experimental methods narrow down the validation space because of extremely high cost, low success rate, and time consumption. Therefore, various computational models have been exploited to infer DTI candidates. METHODS: We introduced relevant databases and packages, mainly provided a comprehensive review of computational models for DTI identification, including network-based algorithms and machine learning-based methods. Specially, machine learning-based methods mainly include bipartite local model, matrix factorization, regularized least squares, and deep learning. RESULTS: Although computational methods have obtained significant improvement in the process of DTI prediction, these models have their limitations. We discussed potential avenues for boosting DTI prediction accuracy as well as further directions.


Assuntos
Algoritmos , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Simulação por Computador , Bases de Dados Factuais , Aprendizado de Máquina , Software
15.
Artigo em Inglês | MEDLINE | ID: mdl-31125928

RESUMO

The colchicine binding site of tubulin is often used to screen the anti-mitotic compounds, which are widely used as anti-cancer therapies. In the present work, an affinity probe capillary electrophoresis (APCE) method was developed for determining the affinity of anti-mitotic compounds. To this end, a fluorescently labeled affinity probe, 5-carboxyfluorescein-colchicine (F-colchicine), was prepared for the affinity competition experiment. The probe can form a stable complex with tubulin with the binding stoichiometry of 0.75, and the dissociation constant Kd of the complex was determined as 5.7 × 10-5 mol/L. In the affinity competition experiment, F-colchicine was incubated with tubulin and the test compound in the solution. The F-colchicine-tubulin complexes and free F-colchicine were quickly separated by CE and the concentration of free F-colchicine was accurately determined with the laser induced fluorescence detection. The affinity constant of the tested compound can be measured with the affinity competition binding curve. The enantiomers of the anti-mitotic compound were evaluated by using the method. The binding affinity of the enantiomers displayed an enantioselective manner. Compared to other affinity binding assay methods, our method is more straightforward, more accurate, and more cost-effective.


Assuntos
Antimitóticos , Colchicina/metabolismo , Descoberta de Drogas/métodos , Eletroforese Capilar/métodos , Tubulina (Proteína)/metabolismo , Antimitóticos/análise , Antimitóticos/química , Antimitóticos/metabolismo , Sítios de Ligação , Colchicina/química , Fluoresceínas/química , Corantes Fluorescentes/química , Ligação Proteica , Reprodutibilidade dos Testes , Tubulina (Proteína)/química
16.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052500

RESUMO

Biologically active chemical compounds may provide remedies for several diseases. Meanwhile, Machine Learning techniques applied to Drug Discovery, which are cheaper and faster than wet-lab experiments, have the capability to more effectively identify molecules with the expected pharmacological activity. Therefore, it is urgent and essential to develop more representative descriptors and reliable classification methods to accurately predict molecular activity. In this paper, we investigate the potential of a novel representation based on Spherical Harmonics fed into Probabilistic Classification Vector Machines classifier, namely SHPCVM, to compound the activity prediction task. We make use of representation learning to acquire the features which describe the molecules as precise as possible. To verify the performance of SHPCVM ten-fold cross-validation tests are performed on twenty-one G protein-coupled receptors (GPCRs). Experimental outcomes (accuracy of 0.86) assessed by the classification accuracy, precision, recall, Matthews' Correlation Coefficient and Cohen's kappa reveal that using our Spherical Harmonics-based representation which is relatively short and Probabilistic Classification Vector Machines can achieve very satisfactory performance results for GPCRs.


Assuntos
Descoberta de Drogas/métodos , Aprendizado de Máquina , Receptores Acoplados a Proteínas-G/metabolismo , Algoritmos , Animais , Bases de Dados de Proteínas , Humanos , Máquina de Vetores de Suporte
17.
Methods Mol Biol ; 1966: 175-192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041747

RESUMO

Nuclear receptors act as ligand-activated transcription factors translating ligand signals into changes in gene expression. The 48 members of the superfamily of nuclear receptors identified so far are involved amongst others in maintenance of metabolic balance, inflammation, and cancer. Thus, they hold enormous potential for drug discovery and some nuclear receptors are experiencing considerable academic and industrial interest. Nuclear receptor modulator discovery requires reliable, robust, and economic test systems that allow for high throughput. In this chapter, we discuss the principle, strengths, and advantages of hybrid reporter gene assays for nuclear receptor focused drug discovery and describe how they can be developed, established, and validated.


Assuntos
Bioensaio/métodos , Descoberta de Drogas/métodos , Genes Reporter , Receptores Citoplasmáticos e Nucleares/metabolismo , Linhagem Celular Transformada , Escherichia coli , Humanos , Ligantes
18.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035589

RESUMO

BACKGROUND: Astaxanthin (ATX) is a lipophilic compound found in many marine organisms. Studies have shown that ATX has many strong biological properties, including antioxidant, antiviral, anticancer, cardiovascular, anti-inflammatory, neuro-protective and anti-diabetic activities. However, no research has elucidated the effect of ATX on ionic channels. ATX can be extracted from shrimp by-products. Our work aims to characterize ATX cell targets to lend value to marine by-products. METHODS: We used the Xenopus oocytes cell model to characterize the pharmacological target of ATX among endogenous Xenopus oocytes' ionic channels and to analyze the effects of all carotenoid-extract samples prepared from shrimp by-products using a supercritical fluid extraction (SFE) method. RESULTS: ATX inhibits amiloride-sensitive sodium conductance, xINa, in a dose-dependent manner with an IC50 of 0.14 µg, a maximum inhibition of 75% and a Hill coefficient of 0.68. It does not affect the potential of half activation, but significantly changes the kinetics, according to the slope factor values. The marine extract prepared from shrimp waste at 10 µg inhibits xINa in the same way as ATX 0.1 µg does. When ATX was added to the entire extract at 10 µg, inhibition reached that induced with ATX 1 µg. CONCLUSIONS: ATX and the shrimp Extract inhibit amiloride-sensitive sodium channels in Xenopus oocytes and the TEVC method makes it possible to measure the ATX inhibitory effect in bioactive SFE-Extract samples.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Oócitos/fisiologia , Amilorida/farmacologia , Animais , Descoberta de Drogas/métodos , Canais de Sódio/metabolismo , Xenopus laevis
19.
Expert Opin Ther Pat ; 29(6): 439-453, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092069

RESUMO

INTRODUCTION: Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD). AREAS COVERED: The authors provide an overview of AR-modulating agents from 2012 to 2018. EXPERT OPINION: The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Desenvolvimento de Medicamentos , Descoberta de Drogas/métodos , Humanos , Masculino , Terapia de Alvo Molecular , Patentes como Assunto , Neoplasias da Próstata/patologia , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo
20.
Anal Bioanal Chem ; 411(15): 3257-3268, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31089788

RESUMO

It has been demonstrated that triterpenes in Alismatis rhizoma (Zexie in Chinese, ZX) contributed to the lipid-lowering effect on high-fat diet-induced hyperlipidemia. Alisol B 23-acetate, one of the abundant triterpenes in ZX, was used as the marker of quality control for ZX in Chinese Pharmacopoeia, while it could not reflect the lipid-lowering effect because other triterpenes in ZX also had prominent medicinal efficacy. To identify the significantly bioactive triterpenes in ZX, a multiple reaction monitoring (MRM)-based characteristic chemical profile (CCP)-support vector machine (SVM) model was used to explore the relationship between triterpenes and lipid-lowering effect of ZX. Firstly, the content of 87 targeted triterpenes was quantified by the MRM-based CCP using UHPLC-QTRAP-MS/MS. Secondly, the lipid-lowering effect of 30 ZX samples was assessed by 3T3-L1 preadipocytes. Thirdly, 9 of the 87 triterpenes possessing high mean impact value were identified to have significant lipid-lowering effect via the particle swarm-optimized SVM model. The new SVM model constructed by the 9 triterpenes showed good prediction performance and the overall prediction accuracy reached 81.94%. Finally, the real activity of these triterpenes was partly confirmed and was consistent with the prediction of SVM. These results showed that the method for discovery of triterpenes with prominent lipid-lowering activity in ZX was reliable. The proposed method is expected to provide an efficient and rapid approach for screening of active component and drug discovery in traditional herbs. Graphical abstract.


Assuntos
Alismataceae/química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Rizoma/química , Máquina de Vetores de Suporte , Triterpenos/química , Triterpenos/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Hiperlipidemias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/análise , Camundongos , Espectrometria de Massas em Tandem
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