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CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor gamma Ligands

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Autor(es):
Mottin, Melina ; Souza, Paulo C. T. ; Ricci, Clarisse G. ; Skaf, Munir S.
Número total de Autores: 4
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 18, n. 1 JAN 2017.
Citações Web of Science: 0
Resumo

The peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPAR gamma ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPAR gamma partial agonist that has been shown to promote the ``browning{''} of white adipose tissue. SR1664 is the precursor of the PPAR gamma non-agonist class of ligands that activates PPAR gamma in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were evaluated by examining the behavior of GQ16 and SR1664 free in water and bound to the ligand binding pocket of PPAR gamma using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPAR gamma ligands. (AU)

Processo FAPESP: 12/24750-6 - Relações entre a obesidade e o receptor TLR4: novos estudos através de simulações de dinâmica molecular
Beneficiário:Paulo Cesar Telles de Souza
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 11/22735-7 - Dinâmica molecular do receptor ativador da proliferação de peroxissomo: associação com ligantes e proteínas Corregulatórias
Beneficiário:Melina Mottin
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 13/08293-7 - CECC - Centro de Engenharia e Ciências Computacionais
Beneficiário:Munir Salomao Skaf
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs