J Chem Inf Model - Discovery of a novel selective PPAR ligand with partial agonist binding properties by integrated in silico/in vitro work flow.

Tópicos

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Resumo

Full agonists to the peroxisome proliferator-activated receptor (PPAR), such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPAR is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPAR ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore- and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies. Hit compound 9 was identified as the most potent ligand (IC50 = 0.3 ?M) and a relatively poor inducer of adipocyte differentiation. The binding mode of compound 9 was confirmed by molecular dynamics simulation, and the calculated free energy of binding was -8.4 kcal/mol. A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions. Further studies on the transcriptional regulation properties of compound 9 revealed a gene regulatory profile that was to a large extent unique, however functionally closer to that of a partial agonist.

Resumo Limpo

full agonist peroxisom proliferatoractiv receptor ppar rosiglitazon associ seri undesir side effect weight gain fluid retent cardiac hypertrophi hepatotox nevertheless ppar involv express gene control glucos lipid metabol import target drug type diabet dyslipidemia atherosclerosi cardiovascular diseas effort identifi novel ppar ligand improv pharmacolog profil emphasi shift select ligand partial agonist bind properti toward end appli integr silicoin vitro workflow base pharmacophor structurebas virtual screen zinc librari coupl competit bind transactiv assay adipocyt differenti gene express studi hit compound identifi potent ligand ic m relat poor induc adipocyt differenti bind mode compound confirm molecular dynam simul calcul free energi bind kcalmol novel function group carbonitril group identifi key substitu ligandprotein interact studi transcript regul properti compound reveal gene regulatori profil larg extent uniqu howev function closer partial agonist

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