RESUMO
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Glicina/análogos & derivados , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombina III/química , Cristalografia por Raios X , Fator Xa/química , Fator Xa/metabolismo , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.
Assuntos
Benzamidinas/síntese química , Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores do Fator Xa , Animais , Benzamidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Conformação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
A generalized Kuramoto model of coupled phase oscillators with a slow varying coupling matrix is studied. The dynamics of the coupling coefficients is driven by the phase difference of pairs of oscillators in such a way that the coupling strengthens for synchronized oscillators and weakens for nonsynchronized pairs. The system possesses a family of stable solutions corresponding to synchronized clusters of different sizes. A particular cluster can be formed by applying external driving at a given frequency to a group of oscillators. Once established, the synchronized state is robust against noise and small variations in natural frequencies. The phase differences between oscillators within the synchronized cluster can be used for information storage and retrieval.
Assuntos
Aprendizagem , Redes Neurais de Computação , Plasticidade Neuronal , Oscilometria , Inteligência Artificial , Armazenamento e Recuperação da Informação , Aprendizagem/fisiologia , Memória/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologiaRESUMO
DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 µM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Antineoplásicos/síntese química , Domínio Catalítico , Modelos Moleculares , Dados de Sequência Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/química , Pirazinas/síntese química , Pirazinas/química , Pirazinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfonas/químicaRESUMO
A novel isonitrile derivative was synthesized and used in an Ugi four component coupling reaction to explore aryl group substitution effects on inhibition of the coagulation cascade serine protease factor Xa.