Discovery Of Novel Peroxisome Proliferator-Activated Receptor γ (PPARγ) Scaffolds With Partial Agonist Binding Properties By Integrated In Silico/In Vitro Work Flow

Full agonists to the peroxisome proliferator-activated receptor γ (PPARγ), 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.(1) In an effort to identify novel PPARγ ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Built on structure- and ligand-based computational techniques (2), a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARs. Consequent from application, five novel PPAR scaffolds displaying distinct chemotypes have been identified, namely (AL-21), S-benzyl-N- (phenylacetyl)cysteine (AL-26), bis([1,1'-biphenyl]-4-yloxy)acetic acid (AL-29), N,S-dibenzoylcysteine (AL-31), O-benzyl-N-((benzyloxy)carbonyl)-4-oxohomoserine (AL-35) with good ADME properties. In vitro transactivation assays demonstrated partial agonism of PPARγ by all five compounds. Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific "tiered screen" protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.