Receptores de hormônios da tireóide: estudos computacionais, ressonância plasmônica de superfície e ensaios celulares / Thyroid hormone receptor: computational studies, surface plasmon resonance and cell based assays

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

The thyroid hormone receptors (TRs) are transcriptional factors involved in cell differentiation, development, metabolism and physiological function of most tissues. Many lines of evidence show that several pharmacological actions of TRs might be beneficial in medical therapy, specially those mediated by TR that target important medical conditions like obesity, hypercholesterolemia and diabetes. Additionally, the findings that TR is the predominant isoform in the heart and mediates most of the TRs deleterious cardiovascular effects, stimulated the research for selective TR ligands which could address important medical needs with an acceptable safety profile. In this PhD thesis, studies of the quantitative structure-activity relationships (QSAR) of a dataset of compounds with reported biologic activity for both TR and TR were performed, and statistically significant Hologram QSAR models with good predictive ability for untested compounds were created. In parallel, a careful virtual screening procedure was executed, leading to the selection of 7 compounds which were purchased for the evaluation of their biological activities. Cell transfection and reporter gene assays were developed, validated and used to evaluate the biological activities of these compounds. Finally, a surface plasmon resonance (SPR) assay was developed and used to assess the agonistic activity of these compounds. The SPR technique was also employed in a careful study of the interaction between the ligand binding domain of TR and peptides derived from its coregulators, which included the determination of the kinetic and thermodynamic parameters for this interaction. The results suggest that flexibility plays an important role in the interaction between the receptor and its coregulators, and point out important aspects of experimental design that should be addressed when using TR LBD and its agonists. Furthermore, the methodology described here may be useful for the identification of new TR ligands.

ASSUNTO(S)

receptores dos hormônios da tireóide medicinal chemistry spr thyroid hormone receptors hqsar cell based assays spr virtual screening surface plasmon resonance hqsar ensaios celulares ensaio virtual química medicinal ressonância plasmônica de superfície

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