Role of halogen bonds in thyroid hormone receptor selectivity: pharmacophore-based 3D-QSSR studies.
Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta 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.
Centro de Biotecnologia Molecular Estrutural, Departamento de Fisica e Informatica, Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Av. Trabalhador Sao-Carlense 400, 13560-970 Sao Carlos-SP, Brazil. napoleao@mac.com
Napoleão F
NF
Valadares
Lívia B
LB
Salum
Igor
I
Polikarpov
Adriano D
AD
Andricopulo
Richard C
RC
Garratt
D018360:Crystallography, X-Ray; D006219:Halogens / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013963:Thyroid Hormones / Q000737:chemistry / Q000378:metabolism*
D006219:Halogens; D008024:Ligands; D013963:Thyroid Hormones