Structural Basis for the Improved Potency of Peroxisome Proliferator‐Activated Receptor (PPAR) Agonists

Abstract

The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC(50) of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.

Therapeutic potential of PPARγ natural agonists in liver diseases

“…29 Rasmus 30 demonstrated that the pharmacophore model can be used to select novel PPARs agonists. In addition, Jang and Peng 31,32 identified promising PPARγ agonists on the basis of structure analyses. Since the first time that virtual screening (VS) was used to identify novel PPARγ agonists by Salam et al, 33 more and more researchers have begun using in silico methods alone or combined with other approaches, such as in vivo or in vitro experiments, 34,35 structure analyses 36,37 and some databases, 36 to find novel agonists as potential candidates to treat diseases.…”

Automatic rebuilding and optimization of crystallographic structures in the Protein Data Bank

“…In one of the examples (3HRV), the MolProbity clashscore was improved from the 5th percentile to the 80th percentile. These results show that PDB_REDO can also improve the most recently submitted structures and that current day depositors can benefit from using PDB_REDO pipeline to improve a structure model before it is submitted to the PDB (see for example Peng et al , 2010). …”

The role of FoxO1 and its modulation with small molecules in the development of diabetes mellitus: A review

“…Many reviews have discussed and compiled PPARG ligands (Lamers et al, 2012;Takada & Makishima, 2020). Those include also various metabolites natural products (Grygiel-Górniak, 2014; Wang et al, 2014) and a study about structure to function correlation study (Peng et al, 2010). Trends between agonists and antagonists are also mixture and conflicting, for example in the case of anticancer drug antagonist GW9662 that manage to covalently binds to PPARG (Leesnitzer et al, 2002).…”