Estudo da hidratação do paracetamol usando a dinâmica molecular de Car-Parrinello

Abstract

The paracetamol (or acetaminophen) is a drug very popular and largely used as analgesic and antipyretic for both adults and children. Since the mechanism of action of paracetamol is not completely understood, and that many aspects of chemical and biological structure of a drug can be explained by solute-solvent iteration, this dissertation aims to study the hydration effect on geometric and electronic parameters of paracetamol and, therefore, contributing in the understanding of the molecular mechanisms related to the chemical and biological activity of this medication. The interactions of paracetamol with water molecules was carried out using Car-Parrinello molecular dynamics method with plane waves as basis set functions with an energy cutoff of 25 Ry and 200 Ry cutoff was used for the expansion of the charge density. All the calculations were carried out using the ultrasoft pseudopotentials of Vanderbilt, wavefunction fictitious mass was set to be 450 a.u., and the exchange-correlation functional used was the PBE. The equations of motion were integrated using the Verlet algoritm with a time step of 5 au (0,121 ƒs), and the trajectory sampling were taken at every 10 steps (1,21 ƒs). Two trajectories were built: one containing isolate paracetamol and the other containing paracetamol and 108 water molecules, both placed in cubic box 16 Å and 15 Å, respectively. The trajectories were simulated for 37 ps for the isolated system and 41 ps for the solvated. The trajectory temperatures were controlled at 300K by the NoséHoover thermostat with a frequency of 50 THz. The results showed that hydration changes the geometric parameters of paracetamol showing that it interacts extensively with water in their hydrophilic groups. The group -CH3 and the benzene ring are not significantly affected by the aqueous solution, showing their hydrophobic nature. This study showed that paracetamol makes several hydrogen bonds with water molecules that affect its geometrical and electronic parameters and, in addition, considering that the drugs biochemical activity occurs, essentially, in aqueous medium, this study can help us to understand influence of the interaction paracetamol-water chemistry and biological activity of the drug.