Virtual Screening Of Lead Compound Based On Pparα/γ/δ Multi-Targets

Objective: Peroxisome proliferator-activated receptors(PPARs)participate in nutrition and energy metabolism,and regulate cellular and systemic energy homeostasis during lipid and carbohydrate metabolism,cell growth,and cancer development.Current drug research is continuously pursuing PPARs ligands with stronger therapeutic effects and higher safety factors.On one hand,compounds with dual PPARα/γ activity have been proposed,and the benefits of insulin sensitization and lipid lowering are combined into one drug,allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications.On the other hand,inhibitors of the PPARs-mediated fatty acid oxidation(FAO)pathway can be used to treat a variety of tumor cells.Considering the involvement of PPARα/δ in oxidative stress homeostasis,tumor-associated macrophage differentiation,angiogenesis,and epithelial-mesenchymal transition,exploring the clinical feasibility of PPARα/δ antagonists in cancer treatment may yield fruitful results.In our research,computer-aided drug design methods were used to screen and design compounds with dual activity of PPARs,aiming at obtaining drugs with hypoglycemic or anticancer effects.Methods: 1.The SYBYL-X2.1 software was used to carry out 3D-QSAR research on 41 compounds with dual PARα/γ agonistic activity.The new compounds were designed based on the structure-activity relationship analysis.Through molecular docking and molecular dynamics simulations,the new compounds were further analyzed to obtain molecules with predicted activity and docking scores higher than the original ligands.2.SYBYL-X2.1 software was used to study 35 PPARα/δ dual antagonists through Co MFA/Co MSIA method to reveal the structure-activity relationship of these molecules.Based on the 3D-QSAR contour map and docking analysis,a series of new compounds were designed and their ADMET properties were predicted.New PPARα/δ dual antagonists with good biological activity and physicochemical properties were obtained.3.Discovery Studio 3.5 software was used to screen 22949 small molecules in Ligand Expo Components-pub database by pharmacophore-based virtual screening method.Structural analysis and structural modification were performed on the compounds that were better than the original ligands,and a series of compounds with novel structures were designed.Through precise docking,ADMET prediction,and molecular dynamics simulation,compounds with PPARα/γ dual agonistic activity were obtained.Results: 1.Through 3D-QSAR studies on a series of compounds with PPARα/γ dual agonistic activity,the structure-activity relationship of 2-(oxazol-4-ylmethyl-2,6-dimethylphenoxy)-2-methylpropionic acid derivatives was obtained.Twelve new compounds with higher predicted activity were obtained by structural modification.Successful molecular design validated the superiority of the model.Eleven of these compounds showed superior molecular docking and molecular dynamics properties and could be further studied as lead compounds of PPARα/γ dual agonists.2.The docking analysis and structure-activity relationship model of the reported triazolone ring derivatives with PPARα/δ dual antagonistic activity were performed to obtain the effect of different positions and types of substituents on the activity of compounds,and the transformation was based on these.Twenty-eight new compounds with higher predictive activity were obtained.Further analysis showed that 19 newly designed compounds had good physicochemical properties,weaker side effects and lower toxicity,which could be further analyzed as lead of PPARα/δ dual antagonists.3.Through the pharmacophore based virtual screening of Ligand Expo Components-pub database,12 compounds with novel structures were obtained.Structural analysis and modification of these compounds resulted in a series of new compounds with a sulfonamide and benzene ring as linker.Through molecular docking,ADMET prediction and molecular dynamics simulation,we finally obtained 9 new PPARα/γ dual target compounds with stable interaction with the targets,low toxicity and side effects,and drug-like properties.Conclusion: In this paper,the virtual screenings of lead compounds based on PPARα/γ/δ targets were conducted,using molecule docking,3D-QSAR research,pharmacophore construction and other computer-aided drug design methods.A series of new PPARs multi-target compounds were found.The research provided valuable lead compounds for the development of new drugs.