Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening,...

PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the combination with structure-based design, synthesis and biological evaluation both in vitro and in vivo, leading to the identification of a potent candidate YG-C-20 as the SPPARγM with improved and safer anti-diabetic therapeutics. Mechanistically, this compound presented such desired pharmacological profiles (e.g., preferable anti-diabetic efficiencies and minimized side effects) mainly via selectively inhibiting the CDK5-mediated phosphorylation of PPARγ-Ser273 and up-regulating the expression of insulin-sensitive genes Adiponectin and Glut4, yet lacking the classical full agonism to induce the adipogenesis and the expression of key adipogenic genes including PPARγ, aP2, CD36, LPL, C/EBPα and FASN. Further validation led to the final recognition of its (R)-configured isomer as the potential conformational form. Subsequent molecular docking studies revealed a unique hydrogen-bonding network of (R)-YG-C-20 with three full PPARγ agonism-unrelated residues, especially with PPARγ-Ser273 phosphorylation-associated site Ser342, which not only gives a clear verification for our structure-based design but also provides a proof of concept for the abovementioned molecular mechanism.