Mechanisms of Nelumbinis folium targeting PPARγ for weight management: A molecular docking and molecular dynamics simulations study

Abstract

The lotus leaf, Nelumbinis folium (NF), has frequently appeared in obesity clinical trials as an intervention to promote weight loss and improve metabolic profiles. However, the molecular mechanisms by which it interacts with important obesity targets and pathways, such as the peroxisome proliferator-activated receptor gamma (PPARγ) within the PPAR signalling pathway, were not well understood. This study aims to screen for candidate compounds from NF with desirable pharmacokinetic properties and examine their binding feasibility at the PPARγ ligand-binding domain (LBD). Ligand- and structure-based screening of NF compounds were performed, and a consensus approach has been applied to identify druggable candidates. By examining the pharmacokinetic profiles, a large proportion of NF compounds exhibited favourable drug-likeness and oral bioavailability properties. Furthermore, the binding affinity scores and poses provided new insights on the distinctive binding behaviours of NF compounds at the LBD of PPARγ in its inactive form. Several NF compounds could bind strongly to PPARγ at sub-pockets where partial agonists and antagonists were found to bind and may induce conformational changes that influence co-repressor binding, trans-repression, and gene expression inhibition. Subsequent molecular dynamics simulations of a candidate compound (NF129 narcissin) bound to PPARγ revealed conformational stability, residue fluctuation, and binding behaviours comparable to that of the known inhibitor, SR1664. Therefore, it can be proposed that narcissin exhibits characteristics of a PPARγ antagonist. Further experimental validation to support the development of NF129 as a future anti-obesity agent is warranted.

Keywords: Binding free energy; Essential dynamics; Ligand-based virtual screening; Narcissin; Structure-based virtual screening; Time-series analysis.