Targeting lipid-sensing nuclear receptors PPAR (α, γ, β/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists

by Selleckchem | Oct 19 2023

The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They can activate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, β/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein-ligand complex (PLC) stability with all the PPARs (α, γ, β/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders.

Comments:

The study aimed to identify novel PPAR pan-agonists from the ZINC database, which could be potential therapeutic targets for metabolic disorders. PPARs are nuclear receptors involved in lipid metabolism, glucose homeostasis, and inflammation regulation. The researchers employed molecular docking and molecular dynamics simulations to screen ligands against the three PPAR isoforms (α, γ, β/δ).

From the screening process, five ligands displayed strong binding affinity to all three PPAR isoforms: eprosartan, canagliflozin, pralatrexate, sacubitril, and olaparib. To assess their pharmacokinetic profiles, an ADMET analysis was performed on these compounds. Among the top five ligands, eprosartan exhibited the best stability in protein-ligand complex (PLC) formation with all PPAR isoforms (α, γ, β/δ). This finding prompted further investigation of eprosartan.

To validate its potential as a PPAR pan-agonist, eprosartan was subjected to MD simulations and compared with lanifibranor, a reference PPAR pan-agonist. The results indicated that eprosartan displayed superior PLC stability with all PPAR isoforms compared to lanifibranor.

To evaluate the practical application of eprosartan, in vitro cell culture models of non-alcoholic fatty liver disease (NAFLD) were utilized. Eprosartan demonstrated a dose-dependent reduction in lipid accumulation and oxidative damage in these models, suggesting its potential as a therapeutic candidate for PPAR-mediated metabolic disorders.

Overall, this study identified eprosartan as a promising PPAR pan-agonist from the ZINC database. Further experimental validation and pharmacological development are warranted to explore its efficacy and safety in treating PPAR-related metabolic disorders.