Structure-based identification of novel PPAR gamma ligands.
Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ and prevent weight gain and fluid retention, showed that a submaximal receptor activation can be a goal in the development of new ligands for PPARγ. Additionally, two previously described receptor antagonists, SR-202 and BADGE, were also shown to improve insulin sensitivity and decrease TNF-α 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 PPARγ. A benzoimidazol acetate, a bromobenzyl-thio-tetrazol benzoate and a [[2-[(1,3-dioxoinden-2-ylidene)methyl]phenoxy]methyl]benzoate were identified as PPARγ ligands, with IC50 values smaller than 10μM. 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 PPARγ binding pocket.
Universidade Federal do ABC, Rua Santa Adelia, 166 Bangu, Santo Andre, SP 09210-170, Brazil.
Flávia M C
FM
da Silva
Jademilson C
JC
dos Santos
Jéssica L O
JL
Campos
Ana Carolina
AC
Mafud
Igor
I
Polikarpov
Ana Carolina M
AC
Figueira
Alessandro S
AS
Nascimento
D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D062313:Databases, Pharmaceutical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
D001562:Benzimidazoles; D001565:Benzoates; D008024:Ligands; D047495:PPAR gamma
Docking; PPAR gamma; Virtual screening