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1.
Angew Chem Int Ed Engl ; 54(22): 6511-5, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-25877959

RESUMO

Structure-based drug design (SBDD) is a powerful and widely used approach to optimize affinity of drug candidates. With the recently introduced INPHARMA method, the binding mode of small molecules to their protein target can be characterized even if no spectroscopic information about the protein is known. Here, we show that the combination of the spin-diffusion-based NMR methods INPHARMA, trNOE, and STD results in an accurate scoring function for docking modes and therefore determination of protein-ligand complex structures. Applications are shown on the model system protein kinase A and the drug targets glycogen phosphorylase and soluble epoxide hydrolase (sEH). Multiplexing of several ligands improves the reliability of the scoring function further. The new score allows in the case of sEH detecting two binding modes of the ligand in its binding site, which was corroborated by X-ray analysis.


Assuntos
Desenho de Fármacos , Ligantes , Proteínas/química , Sítios de Ligação , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Difusão , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas/metabolismo
2.
Acta Neuropathol ; 125(6): 795-813, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23604588

RESUMO

In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrP(Sc)) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.


Assuntos
Encéfalo/efeitos dos fármacos , Doença de Parkinson/terapia , Doenças Priônicas/terapia , Príons/efeitos dos fármacos , Pirazóis/agonistas , Pirimidinas/agonistas , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doenças Priônicas/etiologia , Doenças Priônicas/metabolismo , Príons/metabolismo , Rotenona/farmacologia , alfa-Sinucleína/farmacologia
3.
Chembiochem ; 13(18): 2671-5, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23169772

RESUMO

Arthrofactin, a bioactive cyclic lipopeptide from Pseudomonas sp. MIS38, was reinvestigated for its structural and stereochemical features due to discrepancies between the genetics-based sequence prediction and the currently suggested structure. The structure of arthrofactin and its derivatives was reassigned on the basis of chiral HPLC analysis and extensive NMR and MS experiments. Furthermore, derivatives of arthrofactin were discovered.


Assuntos
Proteínas de Bactérias/química , Biologia Computacional/métodos , Lipopeptídeos/química , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Lipopeptídeos/genética , Lipopeptídeos/metabolismo , Dados de Sequência Molecular , Família Multigênica/genética , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/metabolismo , Filogenia
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