Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nature ; 599(7885): 491-496, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34711951

RESUMO

Protein expression and turnover are controlled through a complex interplay of transcriptional, post-transcriptional and post-translational mechanisms to enable spatial and temporal regulation of cellular processes. To systematically elucidate such gene regulatory networks, we developed a CRISPR screening assay based on time-controlled Cas9 mutagenesis, intracellular immunostaining and fluorescence-activated cell sorting that enables the identification of regulatory factors independent of their effects on cellular fitness. We pioneered this approach by systematically probing the regulation of the transcription factor MYC, a master regulator of cell growth1-3. Our screens uncover a highly conserved protein, AKIRIN2, that is essentially required for nuclear protein degradation. We found that AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes to mediate their nuclear import. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in a highly dynamic, AKIRIN2-dependent process. Cells undergoing mitosis in the absence of AKIRIN2 become devoid of nuclear proteasomes, rapidly causing accumulation of MYC and other nuclear proteins. Collectively, our study reveals a dedicated pathway controlling the nuclear import of proteasomes in vertebrates and establishes a scalable approach to decipher regulators in essential cellular processes.


Assuntos
Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Feminino , Genes myc , Humanos , Masculino , Mitose , Complexo de Endopeptidases do Proteassoma/química , Ligação Proteica , Proteólise
2.
EMBO Mol Med ; 11(8): e9266, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31267692

RESUMO

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.


Assuntos
Inibidores da Angiogênese/farmacologia , Receptores de Apelina/metabolismo , Apelina/metabolismo , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neovascularização Patológica , Inibidores de Proteínas Quinases/farmacologia , Sunitinibe/farmacologia , Animais , Apelina/antagonistas & inibidores , Apelina/deficiência , Apelina/genética , Receptores de Apelina/antagonistas & inibidores , Receptores de Apelina/deficiência , Receptores de Apelina/genética , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/patologia , Metástase Neoplásica , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral
3.
Cell Rep ; 18(9): 2162-2174, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28249162

RESUMO

BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.


Assuntos
Desoxirribonucleases de Sítio Específico do Tipo II/imunologia , Sistema Imunitário/imunologia , Proteínas Nucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , Fatores de Transcrição/imunologia , Animais , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interferon gama/imunologia , Ligantes , Linfoma de Células B/imunologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/imunologia , RNA Mensageiro/imunologia , Transcrição Gênica/imunologia
4.
Genes Dev ; 30(19): 2187-2198, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27737960

RESUMO

Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.


Assuntos
Carcinoma Hepatocelular/genética , Senescência Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Apirase/metabolismo , Carcinoma Hepatocelular/enzimologia , Linhagem Celular , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , RNA Interferente Pequeno/genética
5.
Nature ; 525(7570): 543-547, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26367798

RESUMO

Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.


Assuntos
Azepinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Triazóis/farmacologia , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes myc/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica/genética , Via de Sinalização Wnt/efeitos dos fármacos
6.
J Immunol ; 190(5): 1927-35, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23359496

RESUMO

The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D-interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αßTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220-TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.


Assuntos
Ativação Linfocitária/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/genética , Linfócitos T/metabolismo , Animais , Autoantígenos/genética , Autoantígenos/imunologia , Biomarcadores/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Proteínas Ativadoras de GTPase , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Camundongos , Proteínas do Tecido Nervoso/imunologia , Cultura Primária de Células , Ligação Proteica , Proteínas Proto-Oncogênicas B-raf/imunologia , Proteína Companheira de mTOR Insensível à Rapamicina , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia
7.
Front Biosci (Elite Ed) ; 5(2): 533-45, 2013 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-23277009

RESUMO

Quantitative biology requires high precision measurement of cellular parameters such as surface areas or volumes. Here, we have developed an integrated approach in which the data from 3D confocal microscopy and 2D high-resolution transmission electron microscopy were combined. The volumes and diameters of the cells within one population were automatically measured from the confocal data sets. The perimeter of the cell slices was measured in the TEM images using a semi-automated segmentation into background, cytoplasm and nucleus. These data in conjunction with approaches from stereology allowed for an unbiased estimate of surface areas with high accuracy. We have determined the volumes and surface areas of the cells and nuclei of six different immune cell types. In mast cells for example, the resulting cell surface was 3.5 times larger than the theoretical surface assuming the cell was a sphere with the same volume. Thus, our accurate data can now serve as inputs in modeling approaches in systems immunology.


Assuntos
Células da Medula Óssea/ultraestrutura , Tamanho Celular , Sistema Imunitário/citologia , Células Jurkat/ultraestrutura , Mastócitos/ultraestrutura , Modelos Imunológicos , Biologia de Sistemas/métodos , Animais , Linhagem Celular , Citometria de Fluxo , Humanos , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Transmissão
8.
PLoS One ; 6(7): e22928, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21829558

RESUMO

BACKGROUND: To understand complex biological signalling mechanisms, mathematical modelling of signal transduction pathways has been applied successfully in last few years. However, precise quantitative measurements of signal transduction events such as activation-dependent phosphorylation of proteins, remains one bottleneck to this success. METHODOLOGY/PRINCIPAL FINDINGS: We use multi-colour immunoprecipitation measured by flow cytometry (IP-FCM) for studying signal transduction events to unrivalled precision. In this method, antibody-coupled latex beads capture the protein of interest from cellular lysates and are then stained with differently fluorescent-labelled antibodies to quantify the amount of the immunoprecipitated protein, of an interaction partner and of phosphorylation sites. The fluorescence signals are measured by FCM. Combining this procedure with beads containing defined amounts of a fluorophore allows retrieving absolute numbers of stained proteins, and not only relative values. Using IP-FCM we derived multidimensional data on the membrane-proximal T-cell antigen receptor (TCR-CD3) signalling network, including the recruitment of the kinase ZAP70 to the TCR-CD3 and subsequent ZAP70 activation by phosphorylation in the murine T-cell hybridoma and primary murine T cells. Counter-intuitively, these data showed that cell stimulation by pervanadate led to a transient decrease of the phospho-ZAP70/ZAP70 ratio at the TCR. A mechanistic mathematical model of the underlying processes demonstrated that an initial massive recruitment of non-phosphorylated ZAP70 was responsible for this behaviour. Further, the model predicted a temporal order of multisite phosphorylation of ZAP70 (with Y319 phosphorylation preceding phosphorylation at Y493) that we subsequently verified experimentally. CONCLUSIONS/SIGNIFICANCE: The quantitative data sets generated by IP-FCM are one order of magnitude more precise than Western blot data. This accuracy allowed us to gain unequalled insight into the dynamics of the TCR-CD3-ZAP70 signalling network.


Assuntos
Citometria de Fluxo , Imunoprecipitação , Modelos Biológicos , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anticorpos Monoclonais , Complexo CD3/imunologia , Complexo CD3/metabolismo , Simulação por Computador , Cinética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Teóricos , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Fosforilação , Mapas de Interação de Proteínas , Proteína-Tirosina Quinase ZAP-70/imunologia , Proteína-Tirosina Quinase ZAP-70/metabolismo
9.
Mol Biosyst ; 7(2): 394-402, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21031176

RESUMO

Calorie restriction (CR) is a non genetic intervention, known to confer longevity benefits across the various phyla from unicellular yeast to mammals. CR also invokes homeostatic responses similar to stress, however the sequence of molecular events leading to longevity is still illusive. In this study, we analysed the whole genome gene expression profile in response to CR, mutations mimicking CR, heat shock and H(2)O(2) from a gene ontology perspective. Our analysis revealed that mitochondrion is a common hub in the gene expression programme under these conditions and the electron transport chain (ETC) is a major player. Consequently the genes involved in the metal ion transport were also significantly up-regulated. We confirmed the results of the in silico analysis using quantitative real time PCR which showed up-regulation of genes involved in respiration and transport of iron and copper. The promoter activity of one of the representative genes, FET3, was also found to be higher upon calorie restriction. Altogether, our results indicate that upon calorie restriction the levels of iron and copper fall in cells, which elicits a transcriptional response up-regulating the genes involved in their uptake to maintain cellular homeostasis.


Assuntos
Restrição Calórica , Proteínas de Transporte/genética , Cobre/metabolismo , Ferro/metabolismo , Saccharomyces cerevisiae/genética , Regulação para Cima , Transporte Biológico , Transporte de Elétrons , Perfilação da Expressão Gênica , Genes Fúngicos , Mitocôndrias/metabolismo , Reação em Cadeia da Polimerase , Espectrofotometria Atômica
10.
FEBS Lett ; 584(24): 4832-7, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20828560

RESUMO

The T-cell antigen receptor (TCR) is a multisubunit transmembrane complex that mediates the antigen-specific activation of T cells. Using a variety of techniques, several research groups have shown that TCRs are at least partially pre-clustered before antigen binding. These new findings are contradictory to the "classical" view, according to which TCRs are randomly distributed on the cell surface and only associate upon antigen binding. In this review we try to answer the following questions: What are the experimental evidences for the existence of pre-clustered TCRs? How can the TCR pre-clusters be activated upon antigen binding? Which functional consequences for T-cell activation arise from the pre-clustering of TCRs.


Assuntos
Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Humanos , Ligantes
11.
Immunol Lett ; 130(1-2): 51-6, 2010 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-20005898

RESUMO

Detection of phospho-proteins and differently phosphorylated forms of the same protein are important in understanding cell behaviour. One novel method is Phos-tag SDS-PAGE. A dinuclear Mn(2+) complex that binds to phosphate groups (the Phos-tag) is covalently attached to the polyacrylamide gel matrix. Thus, phosphorylated proteins are retarded in their migration and can be distinguished from their non-phosphorylated counterparts. We applied Phos-tag SDS-PAGE to the analysis of the zeta, CD3epsilon and CD3delta subunits of the T cell antigen receptor (TCR-CD3). Pervanadate stimulation generated six different phospho-zeta and each two different CD3epsilon and CD3delta forms. This corresponds to the phosphorylatable tyrosines on their cytoplasmic tails. The phosphorylation pattern was compatible with random phosphorylation events. Further, we showed that the Phos-tag technology can be applied to Blue Native (BN)-PAGE. This extends the applicability to the analysis of native protein complexes. Upon pervanadate stimulation the TCR-CD3 complex was predominantly detected as two distinct phospho-complexes. In contrast, the B cell antigen receptor (BCR) appeared as one phospho-form. Thus, Phos-tag BN-PAGE is useful for the analysis of different phosphorylation states of multiprotein complexes.


Assuntos
Complexos Multiproteicos/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Receptores de Antígenos de Linfócitos B/química , Animais , Western Blotting , Linhagem Celular , Eletroforese em Gel de Poliacrilamida , Manganês/química , Camundongos , Estrutura Molecular , Fosforilação , Corantes de Rosanilina/química
12.
Curr Pharm Des ; 15(28): 3237-48, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19860673

RESUMO

Vaccination techniques have developed rapidly over the last several decades from the immunization with live attenuated pathogens to the use of peptide and DNA subunit vaccines, from the use of classical adjuvants to cell-directed delivery. Vaccination techiques are also under investigation for the treatment of tumors and autoimmune diseases. However, profound knowledge of activation mechanisms of the immune cells on a molecular level is prerequisite for a better understanding of the immune response, and for the development of effective immunomodulatory tools. In this review we discuss the models of BCR and TCR activation, and using the example of some vacciantion technologies, we show, how the understanding of these models could help in the design of a new generation of vaccines.


Assuntos
Receptores de Antígenos/química , Receptores de Antígenos/imunologia , Vacinas/química , Animais , Autoimunidade/imunologia , Linfócitos B/imunologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Linfócitos T/imunologia
13.
Eur J Med Chem ; 42(4): 463-70, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17083999

RESUMO

A conventional QSAR study has been carried out using thermodynamic and other descriptors, on a set of arylsulfonamidomethylcyclohexyl derivatives as antagonists of potential obesity drug target human neuropeptide Y Y5 receptor. In addition, a novel range based method was applied to obtain a QSAR model so that the information contained in the compounds for which an approximate value instead of exact value of inhibitory activity was available could be included in the model. Analysis of models suggests that range based model is better in screening biologically active compounds from chemical library. The conventional model is able to predict activity accurately only for active compounds whereas the range based method is better in discriminating active and inactive compounds.


Assuntos
Neuropeptídeo Y/química , Neuropeptídeo Y/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Simulação por Computador , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Neuropeptídeo Y/análogos & derivados , Receptores de Neuropeptídeo Y/química , Termodinâmica
14.
Eur J Med Chem ; 41(11): 1339-46, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16884829

RESUMO

A quantitative structure activity relationship (QSAR) analysis has been performed on a data set of 42 aryl heterocycle-based thrombin inhibitors. Several types of descriptors including topological, spatial, thermodynamic, information content and E-state indices were used to derive a quantitative relationship between the anti thrombin activity and structural properties. Genetic algorithm based genetic function approximation method of variable selection was used to generate the model. Best model was developed when number of descriptors in the equation was set to five. Highly statistically significant model was obtained with atom type logP descriptors, logP and Shadow_YZ. The model is not only able to predict the activity of new compounds but also explained the important regions in the molecules in a quantitative manner.


Assuntos
Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Trombina/antagonistas & inibidores , Anticoagulantes/química , Anticoagulantes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Relação Quantitativa Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...