Evaluation of Taraxacum officinale phytoconstituents as potential JNK1 inhibitors : perspectives from ADMET, molecular docking, molecular dynamics, and density functional theory

Abstract

The impact of activated c-Jun N-terminal kinase isoform JNK1 chemical pathways in insulin biosynthesis poses a potential health risk of glucose intolerance. Blocking the activity of JNK1 is a promising route for the design of anti-diabetic drugs and associated metabolic syndromes. In this study, 17 extracts of Taraxacum officinale were chosen to bind JNK1 and ascertain their modulatory activity. We employed molecular dynamics, density functional theory and three docking approaches: standard precision, extra precision and quantum polarized ligand docking. The best binding free energy results were obtained from the quantum polarized ligand docking, with myricetin (1) showing a docking score of -10.464 kcal/mol, while quercetin (2) and daphnetin (3) displayed values of -9.769 and -7.136 kcal/mol respectively. Following this, 100 ns molecular dynamics simulations with Desmond showed stabilization average root mean square deviations of 2.34, 2.87, and 2.88 Å for myricetin, quercetin and daphnetin. Further, molecular dynamics revealed complexes of myricetin (ΔG = -38.81 kcal/mol) and quercetin (ΔG = -34.99 kcal/mol) as the most stable inside the JNK1 interface. The energy gaps for myricetin, quercetin and daphnetin were estimated to be 6.17, 6.00 and 6.53 eV employing the M06–2X functional in PCM solvation. Further, myricetin showed the strongest intramolecular hydrogen bonding with -13.06 kcal/mol. This study provides insights into possible anti-type-2 diabetes properties of Taraxacum officinale targeting JNK1.