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


Autoria(s): VALADARES, Napoleao F.; SALUM, Livia B.; POLIKARPOV, Igor; ANDRICOPULO, Adriano Defini; GARRATT, Richard Charles
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

20/10/2012

20/10/2012

2009

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.

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The State of Sao Paulo Research Foundation (FAPESP)[2008/58316-5]

The State of Sao Paulo Research Foundation (FAPESP)[1998/14138-2]

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The National Council for Scientific and Technological Development (CNPq)[150430/2009-4]

Identificador

JOURNAL OF CHEMICAL INFORMATION AND MODELING, v.49, n.11, p.2606-2616, 2009

1549-9596

http://producao.usp.br/handle/BDPI/29911

10.1021/ci900316e

http://dx.doi.org/10.1021/ci900316e

Idioma(s)

eng

Publicador

AMER CHEMICAL SOC

Relação

Journal of Chemical Information and Modeling

Direitos

restrictedAccess

Copyright AMER CHEMICAL SOC

Palavras-Chave #MOLECULAR DOCKING #LIGAND-BINDING #3D QSAR #BETA #DESIGN #CHOLESTEROL #DISCOVERY #AFFINITY #AGONISTS #SERIES #Chemistry, Multidisciplinary #Computer Science, Information Systems #Computer Science, Interdisciplinary Applications
Tipo

article

original article

publishedVersion