Design and identification of partial Peroxisome proliferator activated receptor gamma (PPARγ) agonists using the synthetic analog of Tetrahydrocannabinol (THC) ajulemic acid (AJA) scaffold as a lead molecule

Abstract

PPARγ is a druggable target for the management of diabetes and inflammatory disease. Total agonism of this receptor produced clinically significant adverse effects, resulting in the withdrawal of entire drug classes specifically the glitazones from the market. The main objective of the study were; to use the bioactive conformation of AJA as lead molecule to probe the PPAR LBP. To identify critical interactions responsible for affinity and stability at this locus, identify optimal structures and validate their utility through molecular dynamics simulation. PDB crystallographic depositions, 20M9 and 4XUM describing bound coordinates of PPARγ bound to AJA and indomethacin respectively were recruited. The small molecules were extracted, and their bioactive coordinates were superimposed to generate a consensus pharmacophore. This was submitted as a query to the ZincPharmer® database. The idealised PPARγ LBP was modelled. The hits from the VS exercise were filtered for Lipinski Rule compliance, docked and ranked in order of affinity. A de novo approach was carried out where seeds retaining the critical fragments were modelled computationally. This study yielded 2 lead like molecular cohorts with high affinity for the PPAR. A cohort of 44,276 and 8 high affinity Lipinski Rule compliant molecules with known synthetic pathways were identified and grouped according to pharmacophoric similarity from the VS and de novo approach respectively. The highest ranked structures (n=5) were proposed for molecular dynamics. The selected structures provide guidance to understanding of partial agonism, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.