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Structure-based druggability assessment of the mammalian structural proteome with inclusion of light protein flexibility.
Loving, Kathryn A; Lin, Andy; Cheng, Alan C.
Afiliação
  • Loving KA; Schrödinger LLC, New York, New York, United States of America.
  • Lin A; Amgen Inc., South San Francisco, California, United States of America.
  • Cheng AC; Amgen Inc., South San Francisco, California, United States of America.
PLoS Comput Biol ; 10(7): e1003741, 2014 Jul.
Article em En | MEDLINE | ID: mdl-25079060
ABSTRACT
Advances reported over the last few years and the increasing availability of protein crystal structure data have greatly improved structure-based druggability approaches. However, in practice, nearly all druggability estimation methods are applied to protein crystal structures as rigid proteins, with protein flexibility often not directly addressed. The inclusion of protein flexibility is important in correctly identifying the druggability of pockets that would be missed by methods based solely on the rigid crystal structure. These include cryptic pockets and flexible pockets often found at protein-protein interaction interfaces. Here, we apply an approach that uses protein modeling in concert with druggability estimation to account for light protein backbone movement and protein side-chain flexibility in protein binding sites. We assess the advantages and limitations of this approach on widely-used protein druggability sets. Applying the approach to all mammalian protein crystal structures in the PDB results in identification of 69 proteins with potential druggable cryptic pockets.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ligação Proteica / Conformação Proteica / Preparações Farmacêuticas / Proteínas / Proteoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ligação Proteica / Conformação Proteica / Preparações Farmacêuticas / Proteínas / Proteoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article