Poster Presentation ANZOS Annual Scientific Meeting 2021

In silico screening and prediction of Nelumbinis Folium compounds targeting PPARγ for weight management (#246)

Ann Rann Wong 1 , Andrew Hung 2 , Angela Wei Hong Yang 1 , Harsharn Gill 2 , George Binh Lenon 1
  1. School of Health and Biomedical Science, RMIT University, Melbourne, Victoria, Australia
  2. School of Science, RMIT University, Melbourne, Victoria, Australia

Obesity is a growing health concern as its prevalence nearly tripled in the past 50 years. Efforts to develop anti-obesity pharmacotherapy have been emerging and among the various drug targets, peroxisome proliferator-activated receptor γ (PPARγ) has attracted attention due to its key role in governing thermogenesis, lipid accumulation, and glucose homeostasis. In this study, we aimed to explore the potential use of phytochemicals from Nelumbinis Folium (NF) to manage obesity and metabolic syndrome. A total of 154 NF compounds comprehensively retrieved from pharmacological databases were subjected to computational high-throughput screening for their ability to target PPARγ (PDB: 5lsg). It is demonstrated, through focused docking, that the highest-binding compounds exhibited greater affinities to the active conformation (Procyanidin B6 -9.8kcal/mol, Rutin -9.8kcal/mol and Procyanidin B8 -9.5kcal/mol) compared to the inactive conformation (3-epi-beta-Sitosterol -8.8kcal/mol, (r)-aporphine -8.6kcal/mol, and beta-Sitosterol -8.5kcal/mol). By analysing ligand-residue interactions, we hypothesise Procyanidin B6 as a putative agonist due to its ability to form hydrogen bonds with Tyr473 on helix H12 and interacting with surrounding residues on H3 and H11, thereby stabilising the activation function-2 (AF-2) domain of PPARγ. Two partial agonists were proposed: Rutin and Procyanidin B8, as they bind favourably in the orthosteric pocket, however no hydrogen-bonding interactions with AF-2 residues were observed. Furthermore, 3-epi-beta-Sitosterol and beta-Sitosterol were predicted as antagonists as they appear to interrupt the formation of AF-2 surface domain by forming primarily hydrophobic contacts with residues in H12. This physical occlusion by putative antagonists at the C-terminus may prevent transactivation of genes involved in adipocyte differentiation and lipid accumulation. Overall, this study proposes several NF compounds which may ameliorate obesity risk factors by suppressing fatty acid storage and modulating glucose metabolism. Further molecular dynamic simulations, as well as in vitro and in vivo studies are required to validate the potential anti-obesity effects of NF compounds.