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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Structural modeling of high-affinity thyroid receptor-ligand complexes

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Author(s):
de Araujo, Alexandre Suman [1] ; Martinez, Leandro [2] ; Nicoluci, Ricardo de Paula [1] ; Skaf, Munir S. [2] ; Polikarpov, Igor [1]
Total Authors: 5
Affiliation:
[1] Univ Sao Paulo, Inst Fis Sao Carlos, Grp Cristalog, BR-13560970 Sao Carlos, SP - Brazil
[2] State Univ Campinas UNICAMP, Inst Chem, BR-13084862 Campinas, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS; v. 39, n. 11, p. 1523-1536, OCT 2010.
Web of Science Citations: 12
Abstract

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. (AU)

FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
Grantee:Igor Polikarpov
Support type: Research Projects - Thematic Grants
FAPESP's process: 06/01977-4 - A study of selectivity and affinity of natural and synthetic ligands of thyroid hormone receptor using free energy calculations
Grantee:Alexandre Suman de Araujo
Support type: Scholarships in Brazil - Post-Doctorate