Structural modeling of high-affinity thyroid receptor-ligand complexes

Autor(es)

de Araujo, Alexandre Suman ^[1] ; Martinez, Leandro ^[2] ; Nicoluci, Ricardo de Paula ^[1] ; Skaf, Munir S. ^[2] ; Polikarpov, Igor ^[1]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS; v. 39, n. 11, p. 1523-1536, OCT 2010.
• Citações Web of Science: 12

Resumo

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)

• Processo FAPESP: 06/06831-8 - Simulações de dinâmica molecular dos receptores do hormônio tireoideano
• Beneficiário: Leandro Martinez
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 06/00182-8 - Biofísica estrutural dos receptores nucleares e proteínas relacionadas
• Beneficiário: Igor Polikarpov
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/01977-4 - Estudo da seletividade e afinidade de ligantes naturais e sintéticos ao receptor de hormônio tireoidiano por cálculos de energia livre
• Beneficiário: Alexandre Suman de Araujo
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado