Structure-based drug design of peroxisome proliferator-activated receptor gamma inhibitors: ferulic acid and derivatives.

Peroxisome proliferator-activated receptor gamma (PPARγ), ligand-activated transcription factor, is a key modulator of genes considered in diabetes development as well as treatment. Adipogenesis differentiation through PPARγ, CCAAT-enhancer protein alpha (C/EBPα) is identified as a critical mechanism in fat accumulation and weight gain. Polyphenols studied against adipocyte differentiation is taken up for consistent support and drug discovery. Structure-based drug design found useful to distinguish the underlying mechanism of receptor-ligand interaction and function. In this work, phenolic acids, ferulic acid and its derivatives are used as ligands. Molecular parameters have been set to filter and sort the 34 derivatives from ZINC and PubChem databases. Besides, for affinity and activity identification, troglitazone and resveratrol co-crystallized ligands have been studied. Absorption, distribution, metabolism, elimination and toxicity, density functional theory, highest occupied molecular orbital-lowest unoccupied molecular orbital values and docking scores define the drug candidate as a potential inhibitor. Residues Ser 342 and Arg 280 bind with the ligands by forming hydrogen bonds and hydrophobic contacts. Based on the docking score, pharmacophore properties and functional energy values of the top six compounds are chosen for molecular dynamics and simulation. Consistency and stability maintained throughout the simulation up to 50 ns were observed. Free binding energy values and standard deviation of receptor and ligand calculated using molecular mechanics-generalized Born and surface area solvation method (MM_GBSA) is found significant. Therefore, ferulic acid derivatives and phenolic acids could be a potential inhibitor for adipocyte differentiation and lipid accumulation.Communicated by Ramaswamy H. Sarma.