Role of halogen bonds in thyroid hormone receptor selectivity: pharmacophore-based 3D-QSSR studies.

Abstract:

: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.

journal_name

J Chem Inf Model

authors

Valadares NF,Salum LB,Polikarpov I,Andricopulo AD,Garratt RC

doi

10.1021/ci900316e

subject

Has Abstract

pub_date

2009-11-01 00:00:00

pages

2606-16

issue

11

eissn

1549-9596

issn

1549-960X

journal_volume

49

pub_type

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