RESUMO
Until recently, one of the major limitations of hydrogen/deuterium exchange mass spectrometry (HDX-MS) was the peptide-level resolution afforded by proteolytic digestion. This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. Owing to the relatively minor amounts of protein required, this technique may be utilised in pharmaceutical development for screening potential therapeutics.
Assuntos
Antineoplásicos/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores Enzimáticos/metabolismo , Modelos Moleculares , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Classe I de Fosfatidilinositol 3-Quinases , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Medição da Troca de Deutério , Avaliação Pré-Clínica de Medicamentos/métodos , Transporte de Elétrons , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Indazóis/química , Indazóis/metabolismo , Indazóis/farmacologia , Peso Molecular , Oligonucleotídeos/antagonistas & inibidores , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Conformação Proteica , Purinas/química , Purinas/metabolismo , Purinas/farmacologia , Piridazinas , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Espectrometria de Massas em Tandem , Triazinas/química , Triazinas/metabolismo , Triazinas/farmacologiaRESUMO
In the 5-year cycle that characterizes a continuous improvement of the US Pharmacopeial (USP) Convention, the Council of the Convention's Section on Global Public Health worked with USP's staff to assess USP's international contributions to date and to consider opportunities for expanding activities that help to ensure good healthcare around the globe.1 This article reviews USP's process and product standards that are used worldwide to ensure the quality of medicines and dietary supplements and to help mitigate the burden of counterfeit and substandard ingredients and products. The article also reviews USP's international programs during the past 5-year cycle, along with continuing and planned international activities.
Assuntos
Medicamentos Falsificados , Suplementos Nutricionais , Contaminação de Medicamentos/prevenção & controle , Fraude/prevenção & controle , Medicamentos Falsificados/análise , Suplementos Nutricionais/análise , Suplementos Nutricionais/normas , Internacionalidade , Controle de Qualidade , Estados UnidosRESUMO
The major metals of potential health concern found in food, drugs (medicines), and dietary supplements are lead, cadmium, mercury, and arsenic. Other metals, such as chromium, copper, manganese, molybdenum, vanadium, nickel, osmium, rhodium, ruthenium, iridium, palladium, and platinum, may be used or introduced during manufacturing and may be controlled in the final article as impurities. Screening for metals in medicines and dietary supplements rarely indicates the presence of toxic metal impurities at levels of concern. The setting of heavy metal limits is appropriate for medicines and is appropriate for supplements when heavy metals are likely or certain to contaminate a given product. Setting reasonable health-based limits for some of these metals is challenging because of their ubiquity in the environment, limitations of current analytical procedures, and other factors. Taken together, compendial tests for metals in food and drugs present an array of issues that challenge compendial scientists.