In silico identification of a potentially novel binding modality for 1,3-dicarbonyl compounds having 2(3h)-benzazolonic heterocycles within the pparγ ligand binding pocket : a de novo design study

Abstract

Rosiglitazone withdrawal from the market has led to a renewed interest in the Peroxisome Proliferator Activated Receptor γ (PPARγ) as target for hypoglycaemic therapy – this time, via partial agonism. This may be achieved by using selective PPARγ modulators such as S-26948. A receptor-based drug design approach was adopted in this study, using the bound conformation of rosiglitazone within the PPARγ ligand binding pocket to identify S-26948 conformers, and consequently generate high affinity novel molecules. S-26948 conformer 17 was chosen, which exhibited an alternative binding modality with respect to rosiglitazone. Ligand binding pocket mapping of this orientation identified a larger pocket with respect to that delineated by the bound coordinates of rosiglitazone, and an additional theoretical novel pocket within PPARγ. Therefore, currently used PPARγ ligands may not occupy the entire breadth of the ligand binding pocket, warranting further investigation from a receptor modality point of view.