Structure-based identification of novel PPAR gamma ligands

Autor(es)

da Silva, Flavia M. C. ^[1] ; dos Santos, Jademilson C. ^[2] ; Campos, Jessica L. O. ^[3] ; Mafud, Ana Carolina ^[2] ; Polikarpov, Igor ^[2] ; Figueira, Ana Carolina M. ^[3] ; Nascimento, Alessandro S. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Fed ABC, BR-09210170 Santo Andre, SP - Brazil

^[2] Inst Fis Sao Carlos, BR-13566570 Sao Carlos, SP - Brazil

^[3] ABTLUS, CNPEM, Lab Nacl Biociencias LNBio, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry Letters; v. 23, n. 21, p. 5795-5802, NOV 1 2013.
• Citações Web of Science: 15

Resumo

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor with an important role in the glucose metabolism and a target for type 2 diabetes mellitus therapy. The recent findings relating the use of the receptor full agonist rosiglitazone and the incidence of myocardial infarction raised concerns regarding whether receptor activation can actually be useful for diabetes management. The discovery of MRL-24 and GQ-16, ligands that can partially activate PPAR gamma and prevent weight gain and fluid retention, showed that a submaximal receptor activation can be a goal in the development of new ligands for PPAR gamma. Additionally, two previously described receptor antagonists, SR-202 and BADGE, were also shown to improve insulin sensitivity and decrease TNF-alpha level, revealing that receptor antagonism may also be an approach to pursue. Here, we used a structure-based approach to screen the subset `Drugs-Now' of ZINC database. Fifteen ligands were selected after visual inspection and tested for their ability to bind to PPAR gamma. A benzoimidazol acetate, a bromobenzyl-thio-tetrazol benzoate and a {[}{[}2-{[}(1,3-dioxoinden-2-ylidene)methyl]phenoxy]methyl] benzoate were identified as PPAR gamma ligands, with IC50 values smaller than 10 mu M. Molecular dynamic simulations showed that the residues H323, H449, Y327, Y473, K367 and S289 are key structural elements for the molecular recognition of these ligands and the polar arm of PPAR gamma binding pocket. (c) 2013 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 10/15376-8 - Estudo prospectivo de ligantes do receptor PPAR gama
• Beneficiário: Alessandro Silva Nascimento
• Modalidade de apoio: Auxílio à Pesquisa - Regular