Understanding the Structural Basis for Inhibition of Cyclin-Dependent Kinases. New Pieces in the Molecular Puzzle.

Levin, Nayara M Bernhardt; Pintro, Val Oliveira; de Avila, Mauricio Boff; de Mattos, Bruna Boldrini; De Azevedo, Walter Filgueira

Levin, Nayara M Bernhardt; Pintro, Val Oliveira; de Avila, Mauricio Boff; de Mattos, Bruna Boldrini; De Azevedo, Walter Filgueira.

Afiliação

Levin NMB; Laboratory of Computational Systems Biology, Faculty of Biosciences - Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681, Porto Alegre-RS 90619-900, Brazil.
Pintro VO; Graduate Program in Cellular and Molecular Biology, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681. Porto Alegre-RS 90619-900, Brazil.
de Avila MB; Laboratory of Computational Systems Biology, Faculty of Biosciences - Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681, Porto Alegre-RS 90619-900, Brazil.
de Mattos BB; Graduate Program in Cellular and Molecular Biology, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681. Porto Alegre-RS 90619-900, Brazil.
De Azevedo WF; Laboratory of Computational Systems Biology, Faculty of Biosciences - Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681, Porto Alegre-RS 90619-900, Brazil.

Curr Drug Targets ; 18(9): 1104-1111, 2017.

Article em En | MEDLINE | ID: mdl-27848884

RESUMO

BACKGROUND: Cyclin-dependent kinases (CDKs) comprise an important protein family for development of drugs, mostly aimed for use in treatment of cancer but there is also potential for development of drugs for neurodegenerative diseases and diabetes. Since the early 1990s, structural studies have been carried out on CDKs, in order to determine the structural basis for inhibition of this protein target. OBJECTIVE: Our goal here is to review recent structural studies focused on CDKs. We concentrate on latest developments in the understanding of the structural basis for inhibition of CDKs, relating structures and ligand-binding information. METHOD: Protein crystallography has been successfully applied to elucidate over 400 CDK structures. Most of these structures are complexed with inhibitors. We use this richness of structural information to describe the major structural features determining the inhibition of this enzyme. RESULTS: Structures of CDK1, 2, 4-9, 12 13, and 16 have been elucidated. Analysis of these structures in complex with a wide range of different competitive inhibitors, strongly indicate some common features that can be used to guide the development of CDK inhibitors, such as a pattern of hydrogen bonding and the presence of halogen atoms in the ligand structure. CONCLUSION: Nowadays we have structural information for hundreds of CDKs. Combining the structural and functional information we may say that a pattern of intermolecular hydrogen bonds is of pivotal importance for inhibitor specificity. In addition, machine learning techniques have shown improvements in predicting binding affinity for CDKs.

Assuntos

Quinases Ciclina-Dependentes/antagonistas & inibidores; Inibidores de Proteínas Quinases/farmacologia; Humanos; Modelos Moleculares; Estrutura Molecular; Inibidores de Proteínas Quinases/química

Palavras-chave

Cyclin-dependent kinase; binding affinity; drug design; inhibitors; machine learning; neurodegenerative disease

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinases Ciclina-Dependentes / Inibidores de Proteínas Quinases Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Curr Drug Targets Assunto da revista: TERAPIA POR MEDICAMENTOS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Brasil País de publicação: Emirados Árabes Unidos

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