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[PMID]:28459556
[Au] Autor:Braga RC; Alves VM; Muratov EN; Strickland J; Kleinstreuer N; Trospsha A; Andrade CH
[Ad] Endereço:Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goiás , Goiânia, GO 74605-170, Brazil.
[Ti] Título:Pred-Skin: A Fast and Reliable Web Application to Assess Skin Sensitization Effect of Chemicals.
[So] Source:J Chem Inf Model;57(5):1013-1017, 2017 05 22.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemically induced skin sensitization is a complex immunological disease with a profound impact on quality of life and working ability. Despite some progress in developing alternative methods for assessing the skin sensitization potential of chemical substances, there is no in vitro test that correlates well with human data. Computational QSAR models provide a rapid screening approach and contribute valuable information for the assessment of chemical toxicity. We describe the development of a freely accessible web-based and mobile application for the identification of potential skin sensitizers. The application is based on previously developed binary QSAR models of skin sensitization potential from human (109 compounds) and murine local lymph node assay (LLNA, 515 compounds) data with good external correct classification rate (0.70-0.81 and 0.72-0.84, respectively). We also included a multiclass skin sensitization potency model based on LLNA data (accuracy ranging between 0.73 and 0.76). When a user evaluates a compound in the web app, the outputs are (i) binary predictions of human and murine skin sensitization potential; (ii) multiclass prediction of murine skin sensitization; and (iii) probability maps illustrating the predicted contribution of chemical fragments. The app is the first tool available that incorporates quantitative structure-activity relationship (QSAR) models based on human data as well as multiclass models for LLNA. The Pred-Skin web app version 1.0 is freely available for the web, iOS, and Android (in development) at the LabMol web portal ( http://labmol.com.br/predskin/ ), in the Apple Store, and on Google Play, respectively. We will continuously update the app as new skin sensitization data and respective models become available.
[Mh] Termos MeSH primário: Alérgenos
Dermatite de Contato
Internet
Pele
Software
[Mh] Termos MeSH secundário: Alérgenos/toxicidade
Animais
Simulação por Computador
Bases de Dados de Compostos Químicos
Seres Humanos
Ensaio Local de Linfonodo
Camundongos
Relação Quantitativa Estrutura-Atividade
Pele/efeitos dos fármacos
Pele/patologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Allergens)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00194


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[PMID]:28816437
[Au] Autor:Mascarenhas R; Le HV; Clevenger KD; Lehrer HJ; Ringe D; Kelleher NL; Silverman RB; Liu D
[Ad] Endereço:Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
[Ti] Título:Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.
[So] Source:Biochemistry;56(37):4951-4961, 2017 Sep 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or γ-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores
Aspartato Aminotransferases/antagonistas & inibidores
Cicloleucina/análogos & derivados
Inibidores Enzimáticos/farmacologia
Modelos Moleculares
Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores
Fosfato de Piridoxal/metabolismo
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/química
4-Aminobutirato Transaminase/metabolismo
Aspartato Aminotransferases/química
Aspartato Aminotransferases/genética
Aspartato Aminotransferases/metabolismo
Sítios de Ligação
Domínio Catalítico
Cristalografia por Raios X
Cicloleucina/química
Cicloleucina/metabolismo
Cicloleucina/farmacologia
Bases de Dados de Compostos Químicos
Bases de Dados de Proteínas
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Proteínas de Escherichia coli/antagonistas & inibidores
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Seres Humanos
Ligantes
Conformação Molecular
Ornitina-Oxo-Ácido Transaminase/química
Ornitina-Oxo-Ácido Transaminase/genética
Ornitina-Oxo-Ácido Transaminase/metabolismo
Conformação Proteica
Fosfato de Piridoxal/química
Piridoxamina/química
Piridoxamina/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Homologia Estrutural de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-amino-4-fluorocyclopentane-1-carboxylic acid); 0 (Enzyme Inhibitors); 0 (Escherichia coli Proteins); 0 (Ligands); 0 (Recombinant Proteins); 0TQU7668EI (Cycloleucine); 5V5IOJ8338 (Pyridoxal Phosphate); 6466NM3W93 (Pyridoxamine); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.13 (Ornithine-Oxo-Acid Transaminase); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00499


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[PMID]:28760531
[Au] Autor:Swellmeen L; Shahin R; Al-Hiari Y; Alamiri A; Hasan A; Shaheen O
[Ad] Endereço:Department of Pharmaceutical Sciences, Faculty of Pharmacy, Zarqa University, Azzarqa, Jordan. Electronic address: lswellmeen@zu.edu.jo.
[Ti] Título:Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors.
[So] Source:Bioorg Med Chem;25(17):4855-4875, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Over expression of Human phosphatidyl inositol mannoside kinases isoform 1 (Pim-1 kinase) has been reported in several leukemia and solid tumors. Our continuous interest to reveal the secrecies of the mysterious Pim-1 kinase binding pocket has led us to employ a structure based drug design procedure based on receptor-ligand pharmacophore generation protocol implemented in Discovery Studio 4.5 (DS 4.5). Subsequently, we collected 104 crystal structures of Pim-1 kinase from the Protein Data Bank (PDB) and used them to generate pharmacophores based on the anticipated co-crystallized ligand-Pim 1 kinase receptor interactions. All selected pharmacophoric features were enumerated and only those that had corresponding valuable receptor-ligand interactions were retained. This was followed by modeling all pharmacophore combinations and scoring them according to their Receiver Operating Characteristic (ROC) curve analysis parameters as well as a DS.4.5 built-in Genetic Function Algorithm (GFA) validating model. Accordingly, 111 pharmacophores resulted with acceptable ROC performances; 1XWS_2_04, 2BIK_2_06, and 1XWS_2_06 (ROC AUC value of: 0.770, 0.743 and 0.741 respectively) were the best pharmacophores. These pharmacophores were employed to guide the synthesis of new series of 7-[(2-Carboxyethyl)amino]-1-substituted-6-fluoro-8-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and their reduced 8-amino derivatives. The synthesized compounds were later evaluated for their Pim-1 kinase inhibitory potencies. Of which the most potent illustrated an IC value of 0.29µM against Pim-1 kinase.
[Mh] Termos MeSH primário: Desenho de Drogas
Inibidores de Proteínas Quinases/síntese química
Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores
Quinolonas/química
[Mh] Termos MeSH secundário: Área Sob a Curva
Sítios de Ligação
Bases de Dados de Compostos Químicos
Seres Humanos
Simulação de Acoplamento Molecular
Ligação Proteica
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/metabolismo
Estrutura Terciária de Proteína
Proteínas Proto-Oncogênicas c-pim-1/metabolismo
Quinolonas/síntese química
Quinolonas/metabolismo
Curva ROC
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Quinolones); EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE


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[PMID]:28722399
[Au] Autor:Swann ET; Fernandez M; Coote ML; Barnard AS
[Ad] Endereço:Data61 CSIRO , Molecular & Materials Modelling, Door 34, Goods Shed, Village Street, Docklands, Victoria 3008, Australia.
[Ti] Título:Bias-Free Chemically Diverse Test Sets from Machine Learning.
[So] Source:ACS Comb Sci;19(8):544-554, 2017 Aug 14.
[Is] ISSN:2156-8944
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Current benchmarking methods in quantum chemistry rely on databases that are built using a chemist's intuition. It is not fully understood how diverse or representative these databases truly are. Multivariate statistical techniques like archetypal analysis and K-means clustering have previously been used to summarize large sets of nanoparticles however molecules are more diverse and not as easily characterized by descriptors. In this work, we compare three sets of descriptors based on the one-, two-, and three-dimensional structure of a molecule. Using data from the NIST Computational Chemistry Comparison and Benchmark Database and machine learning techniques, we demonstrate the functional relationship between these structural descriptors and the electronic energy of molecules. Archetypes and prototypes found with topological or Coulomb matrix descriptors can be used to identify smaller, statistically significant test sets that better capture the diversity of chemical space. We apply this same method to find a diverse subset of organic molecules to demonstrate how the methods can easily be reapplied to individual research projects. Finally, we use our bias-free test sets to assess the performance of density functional theory and quantum Monte Carlo methods.
[Mh] Termos MeSH primário: Bases de Dados de Compostos Químicos
Aprendizado de Máquina
Modelos Químicos
[Mh] Termos MeSH secundário: Análise por Conglomerados
Análise de Componente Principal
Teoria Quântica
Relação Estrutura-Atividade
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE
[do] DOI:10.1021/acscombsci.7b00087


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[PMID]:28715190
[Au] Autor:Schneider N; Fechner N; Landrum GA; Stiefl N
[Ad] Endereço:Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, 4002 Basel, Switzerland.
[Ti] Título:Chemical Topic Modeling: Exploring Molecular Data Sets Using a Common Text-Mining Approach.
[So] Source:J Chem Inf Model;57(8):1816-1831, 2017 Aug 28.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Big data is one of the key transformative factors which increasingly influences all aspects of modern life. Although this transformation brings vast opportunities it also generates novel challenges, not the least of which is organizing and searching this data deluge. The field of medicinal chemistry is not different: more and more data are being generated, for instance, by technologies such as DNA encoded libraries, peptide libraries, text mining of large literature corpora, and new in silico enumeration methods. Handling those huge sets of molecules effectively is quite challenging and requires compromises that often come at the expense of the interpretability of the results. In order to find an intuitive and meaningful approach to organizing large molecular data sets, we adopted a probabilistic framework called "topic modeling" from the text-mining field. Here we present the first chemistry-related implementation of this method, which allows large molecule sets to be assigned to "chemical topics" and investigating the relationships between those. In this first study, we thoroughly evaluate this novel method in different experiments and discuss both its disadvantages and advantages. We show very promising results in reproducing human-assigned concepts using the approach to identify and retrieve chemical series from sets of molecules. We have also created an intuitive visualization of the chemical topics output by the algorithm. This is a huge benefit compared to other unsupervised machine-learning methods, like clustering, which are commonly used to group sets of molecules. Finally, we applied the new method to the 1.6 million molecules of the ChEMBL22 data set to test its robustness and efficiency. In about 1 h we built a 100-topic model of this large data set in which we could identify interesting topics like "proteins", "DNA", or "steroids". Along with this publication we provide our data sets and an open-source implementation of the new method (CheTo) which will be part of an upcoming version of the open-source cheminformatics toolkit RDKit.
[Mh] Termos MeSH primário: Mineração de Dados/métodos
Bases de Dados de Compostos Químicos
[Mh] Termos MeSH secundário: Algoritmos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00249


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[PMID]:28714692
[Au] Autor:Zhu W; Chen H; Wang Y; Wang J; Peng X; Chen X; Gao Y; Li C; He Y; Ai J; Geng M; Zheng M; Liu H
[Ad] Endereço:University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
[Ti] Título:Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer.
[So] Source:J Med Chem;60(14):6018-6035, 2017 Jul 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound 3m not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R, DDR2, and ALK. Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.
[Mh] Termos MeSH primário: Aminopiridinas/síntese química
Antineoplásicos/síntese química
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Indazóis/síntese química
Neoplasias Pulmonares/tratamento farmacológico
Inibidores de Proteínas Quinases/síntese química
Proteínas Tirosina Quinases/antagonistas & inibidores
Piridinas/síntese química
[Mh] Termos MeSH secundário: Aminopiridinas/farmacocinética
Aminopiridinas/farmacologia
Animais
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Bases de Dados de Compostos Químicos
Desenho de Drogas
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Xenoenxertos
Seres Humanos
Indazóis/farmacocinética
Indazóis/farmacologia
Camundongos
Camundongos Nus
Simulação de Acoplamento Molecular
Transplante de Neoplasias
Fosforilação
Inibidores de Proteínas Quinases/farmacocinética
Inibidores de Proteínas Quinases/farmacologia
Proteínas Tirosina Quinases/metabolismo
Piridinas/farmacocinética
Piridinas/farmacologia
Ratos Sprague-Dawley
Transdução de Sinais
Estereoisomerismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-fluoro-2-(5-(2-hydroxy-1-phenylethylamino)-3-(3-methyl-1H-indazol-5-yl)pyridin-2-yl)phenol); 0 (Aminopyridines); 0 (Antineoplastic Agents); 0 (Indazoles); 0 (Protein Kinase Inhibitors); 0 (Pyridines); EC 2.7.10.1 (Protein-Tyrosine Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00076


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[PMID]:28712298
[Au] Autor:Hall RJ; Murray CW; Verdonk ML
[Ad] Endereço:Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
[Ti] Título:The Fragment Network: A Chemistry Recommendation Engine Built Using a Graph Database.
[So] Source:J Med Chem;60(14):6440-6450, 2017 Jul 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The hit validation stage of a fragment-based drug discovery campaign involves probing the SAR around one or more fragment hits. This often requires a search for similar compounds in a corporate collection or from commercial suppliers. The Fragment Network is a graph database that allows a user to efficiently search chemical space around a compound of interest. The result set is chemically intuitive, naturally grouped by substitution pattern and meaningfully sorted according to the number of observations of each transformation in medicinal chemistry databases. This paper describes the algorithms used to construct and search the Fragment Network and provides examples of how it may be used in a drug discovery context.
[Mh] Termos MeSH primário: Bases de Dados de Compostos Químicos
Descoberta de Drogas/métodos
Preparações Farmacêuticas/química
[Mh] Termos MeSH secundário: Modelos Moleculares
Inibidores de Proteases/química
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
RNA Helicases/antagonistas & inibidores
Bibliotecas de Moléculas Pequenas/química
Proteínas não Estruturais Virais/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NS3 protein, hepatitis C virus); 0 (Pharmaceutical Preparations); 0 (Protease Inhibitors); 0 (Small Molecule Libraries); 0 (Viral Nonstructural Proteins); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.6.4.13 (RNA Helicases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00809


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[PMID]:28671460
[Au] Autor:Soubhye J; Chikh Alard I; Aldib I; Prévost M; Gelbcke M; De Carvalho A; Furtmüller PG; Obinger C; Flemmig J; Tadrent S; Meyer F; Rousseau A; Nève J; Mathieu V; Zouaoui Boudjeltia K; Dufrasne F; Van Antwerpen P
[Ad] Endereço:Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles , Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.
[Ti] Título:Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure.
[So] Source:J Med Chem;60(15):6563-6586, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
[Mh] Termos MeSH primário: Benzimidazóis/farmacologia
Inibidores Enzimáticos/farmacologia
Guanidinas/farmacologia
Peroxidase/antagonistas & inibidores
Quinazolinas/farmacologia
[Mh] Termos MeSH secundário: Benzimidazóis/síntese química
Benzimidazóis/toxicidade
Linhagem Celular
Bases de Dados de Compostos Químicos
Desenho de Drogas
Avaliação Pré-Clínica de Medicamentos
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/toxicidade
Ácido Glutâmico/química
Glutamina/química
Guanidinas/síntese química
Guanidinas/toxicidade
Seres Humanos
Peróxido de Hidrogênio/química
Cinética
Lactoperoxidase/antagonistas & inibidores
Lipoproteínas LDL/química
Modelos Químicos
Simulação de Acoplamento Molecular
Neutrófilos/efeitos dos fármacos
Neutrófilos/metabolismo
Oxirredução
Quinazolinas/síntese química
Quinazolinas/toxicidade
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo(d)imidazole); 0 (2-(7-methoxy-4-methylquinazolin-2-yl)guanidine); 0 (Benzimidazoles); 0 (Enzyme Inhibitors); 0 (Guanidines); 0 (Lipoproteins, LDL); 0 (Quinazolines); 0RH81L854J (Glutamine); 3KX376GY7L (Glutamic Acid); BBX060AN9V (Hydrogen Peroxide); EC 1.11.1.- (Lactoperoxidase); EC 1.11.1.7 (Peroxidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00285


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[PMID]:28669525
[Au] Autor:Shah F; Stepan AF; O'Mahony A; Velichko S; Folias AE; Houle C; Shaffer CL; Marcek J; Whritenour J; Stanton R; Berg EL
[Ad] Endereço:Worldwide Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA. Electronic address: falgunhshah@gmail.com.
[Ti] Título:Mechanisms of Skin Toxicity Associated with Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.
[So] Source:Cell Chem Biol;24(7):858-869.e5, 2017 Jul 20.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series. Investigation of a database of chemicals tested in these systems and transcriptional profiling suggested that the mechanism of toxicity may involve modulation of nuclear receptor targets RAR/RXR, and/or VDR with AhR antagonism. The studies reported here demonstrate how phenotypic profiling of preclinical drug candidates using human primary cells can provide insights into the mechanisms of toxicity and inform early drug discovery and development campaigns.
[Mh] Termos MeSH primário: Fibroblastos/efeitos dos fármacos
Receptor de Glutamato Metabotrópico 5/metabolismo
Dermatopatias/induzido quimicamente
[Mh] Termos MeSH secundário: Regulação Alostérica
Células Cultivadas
Bases de Dados de Compostos Químicos
Dinoprostona/metabolismo
Regulação para Baixo/efeitos dos fármacos
Fibroblastos/citologia
Fibroblastos/metabolismo
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Interleucina-2/metabolismo
Interleucina-6/metabolismo
Lipopolissacarídeos/toxicidade
Ligação Proteica
Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores
Receptor de Glutamato Metabotrópico 5/química
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
Receptores de Hidrocarboneto Arílico/metabolismo
Receptores de Calcitriol/agonistas
Receptores de Calcitriol/metabolismo
Receptores do Ácido Retinoico/agonistas
Receptores do Ácido Retinoico/metabolismo
Dermatopatias/metabolismo
Dermatopatias/patologia
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/toxicidade
Fator de Necrose Tumoral alfa/metabolismo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-2); 0 (Interleukin-6); 0 (Lipopolysaccharides); 0 (Receptor, Metabotropic Glutamate 5); 0 (Receptors, Aryl Hydrocarbon); 0 (Receptors, Calcitriol); 0 (Receptors, Retinoic Acid); 0 (Small Molecule Libraries); 0 (Tumor Necrosis Factor-alpha); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE


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[PMID]:28657314
[Au] Autor:Quéméner A; Maillasson M; Arzel L; Sicard B; Vomiandry R; Mortier E; Dubreuil D; Jacques Y; Lebreton J; Mathé-Allainmat M
[Ad] Endereço:CRCINA, INSERM, CNRS, University of Nantes , Nantes 44007, France.
[Ti] Título:Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization.
[So] Source:J Med Chem;60(14):6249-6272, 2017 Jul 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 ß and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rß chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.
[Mh] Termos MeSH primário: Interleucina-15/antagonistas & inibidores
Ftalazinas/química
Triazóis/química
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Bases de Dados de Compostos Químicos
Seres Humanos
Interleucina-15/química
Interleucina-15/metabolismo
Subunidade beta de Receptor de Interleucina-2/química
Subunidade beta de Receptor de Interleucina-2/metabolismo
Camundongos
Simulação de Acoplamento Molecular
Ftalazinas/síntese química
Ftalazinas/farmacologia
Bibliotecas de Moléculas Pequenas/química
Estereoisomerismo
Relação Estrutura-Atividade
Triazóis/síntese química
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-15); 0 (Interleukin-2 Receptor beta Subunit); 0 (Phthalazines); 0 (Small Molecule Libraries); 0 (Triazoles)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00485



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