Background: Metabolic syndrome is a matrix of different metabolic disorders which are the
leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear
receptor involved in metabolism of fats and glucose.
Objective: In order to explore structural requirements for selective PPAR modulators to control lipid
and carbohydrate metabolism, the multi-cheminformatics studies have been performed.
Methods: In silico modeling studies have been performed on a diverse set of PPAR modulators through
quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies.
Results: It is observed that the presence of an amide fragment (–CONHRPh) has a detrimental effect
while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the
presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage
and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent
and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in
PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation.
Conclusion: Here, the essential structural features have been explored for selective modulation of each
subtype of PPAR in order to design new modulators with improved activity/selectivity.