Density functional and molecular dynamics simulations of local anesthetics in 0.9% NaCl solution

Abstract

We have made density functional calculations and molecular dynamics (MD) simulations to investigate the structure and pharmacological action of local anesthetics: tetracaine, procaine and lidocaine. The MD simulations were made in a NPT ensemble, in a 0.9% NaCl solution, on both unprotonated and protonated forms of the molecules. The radial distribution function was used to study solvent effects in different regions of the molecules. Although all three anesthetics have different degrees of hydrophobicity, the amino-terminals were the mostly affected by the protonation yielding hydrophilic regions. The charged amino-esters present hydrophilicity on the ester as well as amine terminals. Cl− from the solvent solution forms hydrogen bonds via protonated hydrogen attached to nitrogen, yielding neutral molecules, which could, in principle, penetrate the membranes and loose Cl− to act in the protonated form. Density functional theory calculations indicated a change in the electrostatic potential and showed that Cl− weakly binds to the amine hydrogen, what suggests it is a favorable interaction and supports the existence of the hydrochloric forms of these local anesthetics.