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[PMID]:29274493
[Au] Autor:Yang X; Wedajo W; Yamada Y; Dahlroth SL; Neo JJ; Dick T; Chui WK
[Ad] Endereço:Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
[Ti] Título:1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity.
[So] Source:Eur J Med Chem;144:262-276, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR-TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5-triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC : 0.01 µM and MIC : 0.025 µM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy.
[Mh] Termos MeSH primário: Antagonistas do Ácido Fólico/farmacologia
Mycobacterium tuberculosis/enzimologia
Compostos de Espiro/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Feminino
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Células Hep G2
Seres Humanos
Masculino
Microssomos Hepáticos/química
Microssomos Hepáticos/metabolismo
Simulação de Acoplamento Molecular
Estrutura Molecular
Mycobacterium tuberculosis/citologia
Ratos
Compostos de Espiro/síntese química
Compostos de Espiro/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Folic Acid Antagonists); 0 (Spiro Compounds); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


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[PMID]:29384854
[Au] Autor:Gao J; Li X; Chen J; Gong W; Yue K; Wu Z
[Ad] Endereço:Department of Interventional Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
[Ti] Título:Uterine artery embolization combined with local infusion of methotrexate and 5- fluorouracil in treating ectopic pregnancy: A CONSORT-compliant article.
[So] Source:Medicine (Baltimore);97(5):e9722, 2018 Feb.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To compare the efficiency and safety of uterine artery embolization (UAE) combined with local infusion of methotrexate (MTX) or MTX and 5-fluorouracil (5-FU) in the treatment of ectopic pregnancy (EP). METHODS: One hundred women with EP were prospectively enrolled from December 2012 to February 2015 and randomly allocated into 2 groups. One group was treated with UAE combined MTX, and the other with UAE combined with MTX and 5-FU. Local MTX was administrated at a dose of 80 to 120 mg, based on the initial ß-human chorionic gonadotropin (ß-HCG) levels, and 5-FU was given intra-arterially at a uniform dose of 0.5 g. RESULTS: Bilateral UAE was successfully performed in all 100 patients, 88 of whom were clinically successfully treated, 45 (91.8%) in the MTX group, and 43 (87.8%) in the MTX + 5-FU group; 89% of the patients achieved normalization of ß-HCG below 70,000 mIU/mL within 14 to 21 days postoperatively. The time to successful ß-HCG resolution was 26.74 ±â€Š5.57 days for patients receiving MTX + UAE treatment, and 27.57 ±â€Š5.08 days for those treated with additional 5-FU. Six patients had subsequent intramuscular injections of MTX and 6 had a unilateral salpingectomy after the treatment failure. Mild immediate side effects accounted for 24.5% in the sole MTX and 58.3% in MTX + 5-FU group. CONCLUSION: A combination of UAE and intrauterine infusion of MTX showed comparable efficiency to UAE combined with a local infusion of MTX and 5-FU in treating EP patients with the intention to preserve fertility.
[Mh] Termos MeSH primário: Abortivos/uso terapêutico
Fluoruracila/administração & dosagem
Metotrexato/administração & dosagem
Gravidez Ectópica/tratamento farmacológico
Gravidez Ectópica/cirurgia
Embolização da Artéria Uterina
[Mh] Termos MeSH secundário: Adulto
Antimetabólitos/uso terapêutico
Gonadotropina Coriônica/metabolismo
Terapia Combinada
Feminino
Antagonistas do Ácido Fólico/uso terapêutico
Seres Humanos
Injeções Intra-Arteriais
Gravidez
Gravidez Ectópica/metabolismo
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Abortifacient Agents); 0 (Antimetabolites); 0 (Chorionic Gonadotropin); 0 (Folic Acid Antagonists); U3P01618RT (Fluorouracil); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009722


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[PMID]:28865294
[Au] Autor:Ewida MA; Abou El Ella DA; Lasheen DS; Ewida HA; El-Gazzar YI; El-Subbagh HI
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt.
[Ti] Título:Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study.
[So] Source:Bioorg Chem;74:228-237, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC of 0.06µM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC value of 0.8µM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antagonistas do Ácido Fólico/farmacologia
Piridazinas/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Piridazinas/síntese química
Piridazinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Folic Acid Antagonists); 0 (Pyridazines); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


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[PMID]:28806050
[Au] Autor:Santa Maria JP; Park Y; Yang L; Murgolo N; Altman MD; Zuck P; Adam G; Chamberlin C; Saradjian P; Dandliker P; Boshoff HIM; Barry CE; Garlisi C; Olsen DB; Young K; Glick M; Nickbarg E; Kutchukian PS
[Ad] Endereço:Modeling & Informatics, Merck Research Laboratories , Boston, Massachusetts, United States.
[Ti] Título:Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.
[So] Source:ACS Chem Biol;12(9):2448-2456, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.
[Mh] Termos MeSH primário: Antituberculosos/química
Antituberculosos/farmacologia
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/enzimologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Avaliação Pré-Clínica de Medicamentos
Células HeLa
Ensaios de Triagem em Larga Escala
Seres Humanos
Ligantes
Simulação de Acoplamento Molecular
Mycobacterium tuberculosis/crescimento & desenvolvimento
Tuberculose/tratamento farmacológico
Tuberculose/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Folic Acid Antagonists); 0 (Ligands); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00468


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[PMID]:28802357
[Au] Autor:Eren SB; Dogan R; Yenigun A; Veyseller B; Tugrul S; Ozturan O; Aydin MS
[Ad] Endereço:Bezmialem Vakif University, Faculty of Medicine, Department of Otorhinolaryngology, Fatih, Istanbul, Turkey.
[Ti] Título:Evaluation of ototoxicity of intratympanic administration of Methotrexate in rats.
[So] Source:Int J Pediatr Otorhinolaryngol;100:132-136, 2017 Sep.
[Is] ISSN:1872-8464
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Methotrexate is a dihydrofolate reductase enzyme inhibitor with very high selectivity, and it is an antiproliferative folic acid antagonist used for the treatment of autoimmune diseases. In this study, our objective was to evaluate the effect of intratympanic Methotrexate application in the inner ear. METHODS: This study was planned as an animal study. This study performed in a tertiary referral center. 24 healthy female rats were used in our study. They were separated into three groups. 0.2 cc intratympanic saline was applied to both ears of Group 1. Paracentesis was applied to the tympanic membrane in both ears of Group 2. 0.2 cc intratympanic Methotrexate was applied to both ears of Group 3. At the beginning of the study, Distortion-product otoacoustic emissions (DPOAE) and Auditory brainstem response (ABR) of all rats were measured and then again on the 5th, 10th and 15th day. Histologic examinations of all groups were compared. RESULTS: There was not any significant difference between basal DPOAE and ABR measurement values of the groups and the results were measured again on the 5th, 10th and 15th day (p > 0.05). There was no difference between the groups in terms of histology. CONCLUSION: The intratympanic Methotrexate injection does not have any ototoxic effect on inner ear. We assume that intratympanic Methotrexate could be used safely on inner ear diseases in which steroid treatment is contraindicated or not effective.
[Mh] Termos MeSH primário: Otopatias/induzido quimicamente
Antagonistas do Ácido Fólico/efeitos adversos
Metotrexato/efeitos adversos
Membrana Timpânica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos
Feminino
Antagonistas do Ácido Fólico/farmacologia
Metotrexato/farmacologia
Emissões Otoacústicas Espontâneas/efeitos dos fármacos
Ratos
Membrana Timpânica/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Folic Acid Antagonists); YL5FZ2Y5U1 (Methotrexate)
[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:170814
[St] Status:MEDLINE


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[PMID]:28789907
[Au] Autor:Thakkar SS; Thakor P; Ray A; Doshi H; Thakkar VR
[Ad] Endereço:Advanced Organic Chemistry Department, P. D. Patel Institute of Applied Sciences, CHARUSAT, Changa 388421, Gujarat, India.
[Ti] Título:Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities.
[So] Source:Bioorg Med Chem;25(20):5396-5406, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Benzothiazole analogues are of interest due to their potential activity against malarial and microbial infections. In search of suitable antimicrobial and antimalarial agents, we report here the synthesis, characterization and biological activities of benzothiazole analogues (J 1-J 10). The molecules were characterized by IR, Mass, H NMR, C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains; the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds J 1, J 2, J 3, J 5 and J 6 were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR, computational and in vitro studies were carried out to examine their candidatures as lead dihydrofolate reductase inhibitors.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Antifúngicos/farmacologia
Antimaláricos/farmacologia
Benzotiazóis/farmacologia
Antagonistas do Ácido Fólico/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Antifúngicos/síntese química
Antifúngicos/química
Antimaláricos/síntese química
Antimaláricos/química
Benzotiazóis/síntese química
Benzotiazóis/química
Sobrevivência Celular/efeitos dos fármacos
Simulação por Computador
Relação Dose-Resposta a Droga
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Bactérias Gram-Negativas/efeitos dos fármacos
Bactérias Gram-Positivas/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Plasmodium falciparum/efeitos dos fármacos
Teoria Quântica
Schizosaccharomyces/citologia
Schizosaccharomyces/efeitos dos fármacos
Relação Estrutura-Atividade
Tetra-Hidrofolato Desidrogenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 0 (Antimalarials); 0 (Benzothiazoles); 0 (Folic Acid Antagonists); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); G5BW2593EP (benzothiazole)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


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[PMID]:28766937
[Au] Autor:Gabel SA; Duff MR; Pedersen LC; DeRose EF; Krahn JM; Howell EE; London RE
[Ad] Endereço:Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , 111 T. W. Alexander Drive, Research Triangle Park, North Carolina 27709, United States.
[Ti] Título:A Structural Basis for Biguanide Activity.
[So] Source:Biochemistry;56(36):4786-4798, 2017 Sep 12.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metformin is the most commonly prescribed treatment for type II diabetes and related disorders; however, molecular insights into its mode(s) of action have been limited by an absence of structural data. Structural considerations along with a growing body of literature demonstrating its effects on one-carbon metabolism suggest the possibility of folate mimicry and anti-folate activity. Motivated by the growing recognition that anti-diabetic biguanides may act directly upon the gut microbiome, we have determined structures of the complexes formed between the anti-diabetic biguanides (phenformin, buformin, and metformin) and Escherichia coli dihydrofolate reductase (ecDHFR) based on nuclear magnetic resonance, crystallographic, and molecular modeling studies. Interligand Overhauser effects indicate that metformin can form ternary complexes with p-aminobenzoyl-l-glutamate (pABG) as well as other ligands that occupy the region of the folate-binding site that interacts with pABG; however, DHFR inhibition is not cooperative. The biguanides competitively inhibit the activity of ecDHFR, with the phenformin inhibition constant being 100-fold lower than that of metformin. This inhibition may be significant at concentrations present in the gut of treated individuals, and inhibition of DHFR in intestinal mucosal cells may also occur if accumulation levels are sufficient. Perturbation of folate homeostasis can alter the pyridine nucleotide redox ratios that are important regulators of cellular metabolism.
[Mh] Termos MeSH primário: Biguanidas/química
Biguanidas/farmacologia
Hipoglicemiantes/química
Hipoglicemiantes/farmacologia
Tetra-Hidrofolato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalização
Escherichia coli/enzimologia
Escherichia coli/genética
Escherichia coli/metabolismo
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/farmacologia
Modelos Moleculares
Estrutura Molecular
Conformação Proteica
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biguanides); 0 (Folic Acid Antagonists); 0 (Hypoglycemic Agents); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00619


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[PMID]:28711701
[Au] Autor:Tian C; Wang M; Han Z; Fang F; Zhang Z; Wang X; Liu J
[Ad] Endereço:Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
[Ti] Título:Design, synthesis and biological evaluation of novel 6-substituted pyrrolo [3,2-d] pyrimidine analogues as antifolate antitumor agents.
[So] Source:Eur J Med Chem;138:630-643, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of novel 6-substituted pyrrolo[3,2-d]pyrimidine analogues (10a, 11a-13a, 15a, 17a, 18a, 27a and 28a) have been designed and synthesized as antifolate antitumor agents. The anti-proliferative activities of these compounds against HL60, A549, H1299, Hela, HCT116 and HT29 tumor cells were evaluated. Most of the compounds exhibited micromolar anti-proliferative potencies. Compound 15a, the most potent one, has GI value of 0.73, 1.72, and 8.92 µM against A549, H1299 and HL60 cells, respectively. The cell cycle distribution assay displayed that 15a could increase the accumulation of G2/M-phase cells. 15a showed low potency in induction of apoptosis. However, the inhibition of A549 cell colony formation was observed. These indicated that the tumor cell death relied on the irreversible effect of 15a on clonogenicity and cell proliferation. The identification of targeted pathway of 15a implied that the anti-proliferative potencies of 15a probably act through dual inhibition of thymidylate synthase (TS) and dihydrofolate reductase (DHFR).
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Antagonistas do Ácido Fólico/farmacologia
Ácido Fólico/metabolismo
Pirimidinas/farmacologia
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Morte Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Antagonistas do Ácido Fólico/síntese química
Antagonistas do Ácido Fólico/química
Seres Humanos
Estrutura Molecular
Pirimidinas/síntese química
Pirimidinas/química
Pirróis/síntese química
Pirróis/química
Relação Estrutura-Atividade
Tetra-Hidrofolato Desidrogenase/metabolismo
Timidilato Sintase/antagonistas & inibidores
Timidilato Sintase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Folic Acid Antagonists); 0 (Pyrimidines); 0 (Pyrroles); 0 (Pyrrolo(2,3-d)pyrimidine); 935E97BOY8 (Folic Acid); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase); EC 2.1.1.45 (Thymidylate Synthase)
[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:170717
[St] Status:MEDLINE


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[PMID]:28634233
[Au] Autor:Chen D; Jansson A; Sim D; Larsson A; Nordlund P
[Ad] Endereço:From the School of Biological Sciences, Lab 07-02 and.
[Ti] Título:Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states.
[So] Source:J Biol Chem;292(32):13449-13458, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thymidylate synthase (TS) is the sole enzyme responsible for biosynthesis of thymidylate (TMP) and is essential for cell proliferation and survival. Inhibition of human TS (hTS) has been extensively investigated for cancer chemotherapy, but several aspects of its activity and regulation are still uncertain. In this study, we performed comprehensive structural and biophysical studies of hTS using crystallography and thermal shift assay and provided the first detailed structural information on the conformational changes induced by ligand binding to the hTS active site. We found that upon binding of the antifolate agents raltitrexed and nolatrexed, the two insert regions in hTS, the functions of which are unclear, undergo positional shifts toward the catalytic center. We investigated the inactive conformation of hTS and found that the two insert regions are also involved in the conformational transition between the active and inactive state of hTS. Moreover, we identified a ligand-binding site in the dimer interface, suggesting that the cavity in the dimer interface could serve as an allosteric site of hTS to regulate the conformational switching between the active and inactive states. On the basis of these findings, we propose a regulatory mechanism of hTS activity that involves allosteric regulation of interactions of hTS with its own mRNA depending on cellular demands for TMP.
[Mh] Termos MeSH primário: Modelos Moleculares
Timidilato Sintase/metabolismo
[Mh] Termos MeSH secundário: Sítio Alostérico/efeitos dos fármacos
Substituição de Aminoácidos
Sítios de Ligação
Domínio Catalítico/efeitos dos fármacos
Cristalografia por Raios X
Nucleotídeos de Desoxiuracil/química
Nucleotídeos de Desoxiuracil/metabolismo
Dimerização
Ativação Enzimática/efeitos dos fármacos
Estabilidade Enzimática
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/metabolismo
Antagonistas do Ácido Fólico/farmacologia
Seres Humanos
Ligantes
Mutagênese Sítio-Dirigida
Mutação
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Conformação Proteica/efeitos dos fármacos
Dobramento de Proteína/efeitos dos fármacos
Quinazolinas/química
Quinazolinas/metabolismo
Quinazolinas/farmacologia
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Tiofenos/química
Tiofenos/metabolismo
Tiofenos/farmacologia
Timidilato Sintase/antagonistas & inibidores
Timidilato Sintase/química
Timidilato Sintase/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Deoxyuracil Nucleotides); 0 (Folic Acid Antagonists); 0 (Ligands); 0 (Peptide Fragments); 0 (Quinazolines); 0 (Recombinant Proteins); 0 (Thiophenes); 964-26-1 (2'-deoxyuridylic acid); EC 2.1.1.45 (TYMS protein, human); EC 2.1.1.45 (Thymidylate Synthase); FCB9EGG971 (raltitrexed); K75ZUN743Q (nolatrexed)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.787267


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[PMID]:28632788
[Au] Autor:Wambaugh MA; Shakya VPS; Lewis AJ; Mulvey MA; Brown JCS
[Ad] Endereço:Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
[Ti] Título:High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.
[So] Source:PLoS Biol;15(6):e2001644, 2017 Jun.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Anti-Infecciosos Urinários/farmacologia
Farmacorresistência Bacteriana Múltipla
Escherichia coli/efeitos dos fármacos
Klebsiella pneumoniae/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antibacterianos/química
Antibacterianos/uso terapêutico
Anti-Infecciosos Urinários/química
Anti-Infecciosos Urinários/uso terapêutico
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Bioensaio
Biologia Computacional
Desenho de Drogas
Sinergismo Farmacológico
Quimioterapia Combinada
Embrião não Mamífero/efeitos dos fármacos
Embrião não Mamífero/metabolismo
Embrião não Mamífero/microbiologia
Escherichia coli/crescimento & desenvolvimento
Escherichia coli/metabolismo
Infecções por Escherichia coli/tratamento farmacológico
Infecções por Escherichia coli/metabolismo
Infecções por Escherichia coli/microbiologia
Antagonistas do Ácido Fólico/química
Antagonistas do Ácido Fólico/farmacologia
Antagonistas do Ácido Fólico/uso terapêutico
Ensaios de Triagem em Larga Escala
Infecções por Klebsiella/tratamento farmacológico
Infecções por Klebsiella/metabolismo
Infecções por Klebsiella/microbiologia
Klebsiella pneumoniae/crescimento & desenvolvimento
Klebsiella pneumoniae/metabolismo
Testes de Sensibilidade Microbiana
Mutação
Taxa de Mutação
Reconhecimento Automatizado de Padrão
Inibidores da Transcriptase Reversa/química
Inibidores da Transcriptase Reversa/farmacologia
Inibidores da Transcriptase Reversa/uso terapêutico
Bibliotecas de Moléculas Pequenas
Sulfametizol/agonistas
Sulfametizol/química
Sulfametizol/farmacologia
Sulfametizol/uso terapêutico
Trimetoprima/agonistas
Trimetoprima/química
Trimetoprima/farmacologia
Trimetoprima/uso terapêutico
Peixe-Zebra/embriologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Anti-Infective Agents, Urinary); 0 (Bacterial Proteins); 0 (Folic Acid Antagonists); 0 (Reverse Transcriptase Inhibitors); 0 (Small Molecule Libraries); 25W8454H16 (Sulfamethizole); AN164J8Y0X (Trimethoprim)
[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:170621
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2001644



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