2025/01/01 by Ozair Khurram Hashmi, Muhammad Hanzla, Calvin R. Wei +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Drug Transport and Resistance Mechanisms #Inflammatory mediators and NSAID effects #Peroxisome Proliferator-Activated Receptors
paper · pdf · doi:10.36721/pjps.2025.38.4.reg.13103.1
openalex publication_date 2025/01/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/08
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising prevalence, necessitating novel therapeutics. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a promising target for UC management. This study aimed to identify potent, selective PPAR-γ agonists derived from the natural product eucalyptol (1,8-cineole), with reported anti-inflammatory and PPAR-γ activating properties but limited clinical utility. A computational workflow encompassing molecular docking of 342 eucalyptol analogues against PPAR-γ, pharmacokinetic prediction, and molecular dynamics simulations was employed. Docking revealed five top-scoring hits with higher predicted PPAR-γ 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-γ agonist lead for UC therapy, paving the way for experimental validation and optimization of this novel scaffold.