Discovery of a Novel Selective PPARγ Ligand
with Partial Agonist Binding Properties by Integrated <i>in Silico</i>/<i>in Vitro</i> Work Flow
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Abstract
Full agonists to the peroxisome proliferator-activated
receptor
(PPAR)γ, such as Rosiglitazone, have been associated with a
series of undesired side effects, such as weight gain, fluid retention,
cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARγ
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 PPARγ ligands with an improved pharmacological
profile, emphasis has shifted to selective ligands with partial agonist
binding properties. Toward this end we applied an integrated <i>in silico</i>/<i>in vitro</i> 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 <b>9</b> was identified as the most potent ligand (IC<sub>50</sub> = 0.3
μM) and a relatively poor inducer of adipocyte differentiation.
The binding mode of compound <b>9</b> 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 <b>9</b> revealed a gene regulatory profile that
was to a large extent unique, however functionally closer to that
of a partial agonist