Unearthing novel PPAR-? activators: In silico design of eucalyptol analogues for ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising prevalence, necessitating novel therapeutics. The peroxisome proliferator-activated receptor gamma (PPAR-?) is a promising target for UC management. This study aimed to identify potent, selective PPAR-? agonists derived from the natural product eucalyptol (1,8-cineole), with reported anti-inflammatory and PPAR-? activating properties but limited clinical utility. A computational workflow encompassing molecular docking of 342 eucalyptol analogues against PPAR-?, pharmacokinetic prediction, and molecular dynamics simulations was employed. Docking revealed five top-scoring hits with higher predicted PPAR-? binding affinities than eucalyptol. AA051 emerged as the most promising candidate, exhibiting the lowest binding free energies (-31.16 kcal/mol MMGBSA, -16.53 kcal/mol MMPBSA), favorable ADMET profiles including oral bioavailability, solubility, blood-brain barrier permeability, and conformational stability. AA055 also showed a promising binding profile albeit with initial instability. This study highlights computational approaches in drug discovery, identifying AA051 as a compelling PPAR-? agonist lead for UC therapy, paving the way for experimental validation and optimization of this novel scaffold.