Computational investigation of phytochemicals from seeds as modulators of peroxisome proliferator-activated receptor gamma (PPARγ).

Type 2 diabetes mellitus remains global health challenge with involvement of both insulin resistance and dysfunctional insulin secretion from the pancreatic β-cell. Currently, peroxisome proliferator-activated receptor gamma (PPARγ) has been established to play a significant role in glucose homeostasis and insulin sensitization contributing to the pathogenesis of type 2 diabetes mellitus. Hence, this study used in-silico analysis to predict PPARγ antagonists from the natural compounds. ADMET screening, structure-based virtual screening and MM/GBSA calculations of phytochemicals from HPLC analysis of seeds were performed against PPARγ using Maestro Schrodinger suite, followed by the MD simulation of top hit compounds and reference ligand using GROMACS. The quantum chemical calculations of the compounds were performed using Spartan 14 computational chemistry software. The five compounds showed varying degree of binding affinity against PPARγ, the post-docking analysis confirmed strong interaction against the amino acid residues of the binding site of the target. Chlorogenic acid showed the highest docking score (-10.719 kcal/mol) among the compounds comparable to the reference ligand (acarbose = -10.634 kcal/mol). Additionally, MM/GBSA binding free energy (Δ) calculations support the modulatory potential for the docked compounds, which exclusively revealed the highest binding energy for the compounds than the reference ligand (acarbose). The MD simulations suggested the stability of Chlorogenic acid and Quercetin in complex with PPARγ at least in the time period of 90 ns after initial equilibration state with more H-bond observed between the target-hit compounds complex compared to the Acarbose-PPARγ complex. ADMET profile revealed that the five compounds were favorably druggable and promising drug candidates. The quantum chemical calculations showed that the compounds possess better bioactivity and chemical reactivity with favorable intra-molecular charge transfer as electron-donor and electron-acceptor. This study revealed that bioactive compounds especially chlorogenic acid and quercetin identified from seeds demonstrated good modulatory potential against PPARγ compared to acarbose. Therefore, these compounds require further experimental validation for the discovery of new antagonist of PPARγ for developing new anti-diabetes therapy.Communicated by Ramaswamy H. Sarma.