1 research outputs found
Discovery of a Novel Selective PPARĪ³ Ligand with Partial Agonist Binding Properties by Integrated <i>in Silico</i>/<i>in Vitro</i> Work Flow
Full agonists to the peroxisome proliferator-activated
receptor
(PPAR)ĀĪ³, such as Rosiglitazone, have been associated with a
series of undesired side effects, such as weight gain, fluid retention,
cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARĪ³
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 PPARĪ³ 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
Ī¼M) 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
ā8.4 kcal/mol. A novel functional group, the carbonitrile group,
was identified to be a key substituent in the ligandāprotein
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