Razi University

Edaravone is a synthetic antioxidant that has been clinically used for the treatment of acute ischemic stroke and, more recently, for amyotrophic lateral sclerosis. In this study, the tautomer stabilities, geometrical data, HOMO and LUMO orbitals (energy levels and shapes), ??HOMO–LUMO gaps, Mulliken and natural (NPA) atomic charges, dipole moments, global reactivity descriptors and vertical electronic transitions of the Edaravone tautomers were investigated in vacuum and in two media of biological relevance (H2O and Et-OH, described by the integral-equation-formalism polarizable continuum model, IEFPCM), using density functional theory at the B3LYP/6-31G* level. Harmonic vibrational frequency calculations confirmed that all the optimized tautomers are true energy minima and provided the thermochemical corrections from which the standard Gi   free energies were obtained. The optimized geometries were validated against the experimental single-crystal X-ray structure of Edaravone. The obtained results demonstrated the adaptability and coexistence of the tautomers and indicated which tautomer (E1–E3) is preferred over the other tautomeric forms for making the predicted interactions. The thermodynamic stability order E1 > E3 > E2 was obtained in all three media, both at the internal-energy and at the standard Gi   free energy level. Also, the equilibrium constant was applied to investigate the interconversion equilibrium between the different tautomers of Edaravone (E1, E2 and E3) in the selected media. In this study, the molecular docking interactions of the Edaravone tautomers (E1–E3) were also investigated with the selected receptor in order to find the best tautomer for the docking Edaravone–receptor interactions. The docking calculations were carried out with AutoDock Vina against the 5?-nucleotidase enzyme (PDB ID: 2Z1A) and gave binding affinities of ?7.0, ?5.9 and ?7.1 kcal·mol?¹ for E1, E2 and E3, respectively. The amine form (E3) showed the most favourable predicted docking score, although its difference from the keto form (E1) amounts to only 0.1 kcal·mol?¹ and therefore lies within the expected uncertainty of empirical docking scoring functions, whereas the enol form (E2) was clearly the least favourable. The docking results are accordingly interpreted as evidence that the tautomeric state governs the recognition pattern in the binding site, and not as a quantitative ranking of binding affinities.