Structural modeling of high-affinity thyroid receptor-ligand complexes.
Understanding the molecular basis of the binding modes of natural and synthetic ligands to nuclear receptors is fundamental to our comprehension of the activation mechanism of this important class of hormone regulated transcription factors and to the development of new ligands. Thyroid hormone receptors (TR) are particularly important targets for pharmaceuticals development because TRs are associated with the regulation of metabolic rates, body weight, and circulating levels of cholesterol and triglycerides in humans. While several high-affinity ligands are known, structural information is only partially available. In this work we obtain structural models of several TR-ligand complexes with unknown structure by docking high affinity ligands to the receptors' ligand binding domain with subsequent relaxation by molecular dynamics simulations. The binding modes of these ligands are discussed providing novel insights into the development of TR ligands. The experimental binding free energies are reasonably well-reproduced from the proposed models using a simple linear interaction energy free-energy calculation scheme.
de Araujo
Alexandre Suman
AS
Instituto de Física de São Carlos, Universidade de São Paulo, Av Trabalhador SaoCarlense 400, IFSC, Grupo de Cristalografia, PO Box 369, Sao Carlos, SP 13560-970, Brazil.
Martínez
Leandro
L
de Paula Nicoluci
Ricardo
R
Skaf
Munir S
MS
Polikarpov
Igor
I
D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha