Insights into the chirality-dependent recognition of Danshensu Bingpian Zhi stereoisomers with PPARγ

Abstract

Peroxisome proliferator-activated receptor γ (PPAR_γ), a nuclear receptor involved in metabolic processes, inflammation, and energy balance, represents a promising therapeutic target for cardiovascular diseases. Danshensu Bingpian Zhi (DBZ), a chiral compound derived from traditional Chinese medicine, exhibits potential as a PPAR_γ agonist. Using an ensemble-based docking approach, molecular dynamics (MD) simulations, and the molecular mechanics generalized born surface area (MM/GBSA) methods, we explored the binding modes and energetics of DBZ stereoisomers with the PPAR_γ ligand-binding domain (LBD). The results indicated that the right-handed stereoisomer (DBZR) binds like a full agonist, while the left-handed stereoisomer (DBZS) binds as a partial agonist with stronger binding energies (ΔG_bind), indicating a robust interaction with PPAR_γ. Both the stereoisomers stabilize the β-sheet region of PPAR_γ-LBD, potentially protecting Ser245 from phosphorylation by Cdk5, a process implicated in atherosclerosis. Principal component analysis (PCA) and dynamic cross-correlation matrices (DCCM) revealed the complex structural dynamics within the Ω loop, β-sheet, and AF-2 region of PPAR_γ-LBD upon ligand binding, which may contribute to the unique binding mode and efficacy of DBZS. These findings provide insights into the molecular recognition of PPAR_γ-LBD by DBZ stereoisomers and their impact on the conformational dynamics of PPAR_γ, highlighting the therapeutic potential of DBZ and the significance of chirality in drug design.