Molecular Dynamics Study of Uncharged Bupivacaine Enantiomers in Phospholipid Bilayers

M PICKHOLZ; MF MARTINI

Ouro preto

Simposio; XVI Simposio Brasileiro de Química Teórica; 2011

SBQT

Bupivacaine (BVC) is an amino amide local anesthetic with pKa of 8.1. The anesthetic action of bupivacaine is based on its ability to block the voltage gated Na+ channels in the nervous system. The rbupivacaine (in a racemic mixture) was one of the most widely used LA, due to its quality of anesthesia and prolonged duration of action, however it presents high toxicity The enantiomers R-(+) and S-(-) (shown in Fig. 1) presented different activities. Even if both enantiomers are actives as nerve blockers, the R-(+) is more toxic than the S-(-) form. Bupivacaine has a high partition in lipid bilayers. In this way, a good understanding of the interaction of each enantiomer with biological membranes could provide insights to improve their efficacy and minimize the side effects. We have carried out a series of simulations where uncharged DVC, corresponding to the different enantiomers and the racemic mixture, were introduced into a POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine) phospholipids bilayers at molar ratios LA:Lipid of 1:3. The simulations were able to capture important features of the BVC–phospholipid bilayer interactions: our results show that BVC molecules are found in the hydrophobic tail region. The BVC-R enantioner follows a bimodal distribution while the BVC-S is found, in more uniform distribution, at the bilayer center.