In silico and in vitro analysis of PPAR - a / ? dual agonists: Comparative evaluation of potential phytochemicals with anti-obesity drug orlistat

Obesity is an abnormal fat accumulation disorder in the metabolic syndrome constellation, and a risk factor for diabetes, cardiovascular disorders, non-alcoholic fatty liver disease (NAFLD), and cancer. Nuclear receptors (Peroxisome proliferator-activated receptor, PPAR) are implicated in metabolic syndrome and NAFLD, and have potential for therapeutic targeting. Nuclear receptors are ligand-dependent transcription factors that have diverse roles in metabolism, including regulating genes involved in lipid and glucose metabolism, modulating inflammatory genes, and are crucial for maintaining metabolic flexibility. PPAR activates adipose triglyceride lipase, which then releases fatty acids as ligands for PPAR, indicating the interdependency of nuclear receptors and lipases. Here, molecular docking was performed with selected phytochemical ligands that can bind with PPAR-alpha/gamma (PDB ID: 2ZNN and 2ATH, respectively) using Glide module of Schrodinger software followed by molecular dynamics simulation study using Desmond module, and ADMET analysis. Interestingly, orlistat which is a well-known lipase and fatty acid synthase inhibitor also demonstrated favorable binding affinity with both PPAR-alpha/gamma (-10.96 kcal/mol against PPAR alpha and-10.26 kcal/mol against PPAR gamma). The highest docking scores were however shown by the flavonoids -rutin (-14.88 kcal/mol against PPAR alpha and-13.64 kcal/mol against PPAR gamma), and its aglycone, quercetin (-10.08 kcal/mol in PPAR alpha and-9.89 kcal/mol in PPAR gamma). The other phytochemicals (genistein, esculin, daidzin, naringenin, daidzein, dihydroxy coumarin, hydroquinone) showed lower binding affinity as dual agonists. The anti-obesity effects were experimentally validated in cultured adi-pocytes, which revealed better lipid inhibition by rutin and quercetin than orlistat (quercetin > rutin > orlistat) pointing to their strong potential in anti-obesity treatment.

Automated summary

Obesity is a disorder characterized by abnormal fat accumulation and has been linked to metabolic syndrome and various diseases. Nuclear receptors PPAR play a crucial role in metabolism and may be therapeutic targets in obesity. This study identified phytochemical ligands, such as rutin and quercetin, that showed high binding affinity with PPAR and demonstrated anti-obesity effects in experiments.