Identification of Novel PPAR-β/δ Agonists from Kaempferol, Quercetin, and Resveratrol Derivatives by Targeting Cancer: An Integrative Molecular Docking and Dynamics Simulation Approach

Abstract

Background: Drug resistance in cancer is a serious threat to human well-being. There is a dire need to develop novel and efficient lead molecules to treat the disease. In lieu of anti-cancer activities, Peroxisome proliferator–activated receptors (PPARs)-β/δ proven to be potential therapeutic targets against cancer. However, there are yet no PPAR-β/δ agonists reported for clinical use. Objective: The present study features in silico screening and identification of 8708 derivatives based on backbone of natural compounds like Kaempferol, Quercetin and Resveratrol against PPAR-β/δ using molecular docking, and molecular dynamics (MD) simulations. Methods: Initial screening of 8708 derivatives was done by recruiting Lipinski’s rule of five. Docking calculations were assessed through FlexX software tool. GROMACS was used to analyze dynamic perturbations and binding free energy (MM/GBSA) analysis of the top compounds. SwissADME was used to analyze pharmacokinetic properties. Results: The results of molecular docking indicated that 2-[2-(2,4-Dihydroxyphenyl)-2- oxoethoxy]benzoate (DOB), (E)-1-(3,4,5-Trihydroxyphenyl)-3-(3,4-dihydroxyphenyl) propene (TDP) and 2-Hydroxy-3-(2,6,7-trihydroxy-3-oxo-3H-xanthen-9-YL) benzoic acid (HTOB); respective derivatives of Kaempferol, Resveratrol and Quercetin strongly binds to the active site residues of PPAR-β/δ. Furthermore, ADME (absorption, distribution, metabolism & excretion) profile conferred their high druglikeness properties. On monitoring their dynamic perturbations, HTOB acquired the most favorable interaction and stability within the vicinity of PPAR-β/δ protein. Conclusion: These outcomes constitute preliminary studies and the obtained lead derivatives could be great options to treat various types of cancer and formulate as oral drug candidates.