Role of Halogen Bonds in Thyroid Hormone Receptor Selectivity: Pharmacophore-Based 3D-QSSR Studies

Autor(es)

Valadares, Napoleao F. ^[1] ; Salum, Livia B. ^[1] ; Polikarpov, Igor ^[1] ; Andricopulo, Adriano D. ^[1] ; Garratt, Richard C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Dept Fis & Informat, Ctr Biotecnol Mol Estrutural, BR-13560970 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 49, n. 11, p. 2606-2616, NOV 2009.
• Citações Web of Science: 35

Resumo

Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TR alpha and TR beta. Several pharmacological effects mediated by TR beta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TR beta activation may elicit these effects while maintaining an acceptable safety profile, To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics. (AU)

• Processo FAPESP: 08/58316-5 - Estudos cinéticos e funcionais das proteínas humanas da família septina
• Beneficiário: Napoleão Fonseca Valadares
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 98/14138-2 - Center for Structural Molecular Biotechnology
• Beneficiário: Glaucius Oliva
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs