Local Anesthetics-Phospholipid Membranes Interactions by Molecular Dynamics

M. PICKHOLZ

La Plata

Workshop; 2da Escuela de Nanomedicinas; 2010

Local Anesthetics-Phospholipid Membranes Interactions by Molecular Dynamics Simulations     Mónica Pickholz   aDepartment of Pharmaceutical Technology, Universidad de Buenos Aires, Junin 954 RA-1053, Buenos Aires,Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).               Relief of localized pain is a challenging problem in medical and odontological research. Local anesthetic agents used to relieve pain symptoms are characterized by limited duration of analgesia and may result in both systemic and local toxicity. However, many of the pharmacological properties of conventional drugs can be improved through the use of drug delivery systems, which include particulate carriers, composed primarily of lipids and/or polymers, and their associated therapeutics.  For instance, local anesthetics encapsulated in liposomes have shown to gradual release the drug, obtaining a prolonged duration of the anesthetic action and reducing the central nervous and/or cardiovascular system toxicity [1]. In this work, we investigate the interaction of Prilocaine (PLC) – an aminoamide local anesthetic– with model membranes by Molecular Dynamics (MD) simulations. PLC has a pKa of 7.9, therefore their charged and uncharged forms are relevant at physiological pH. In this way, we have carried out a series of simulations where charged and uncharged  PLC were introduced into a POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine) phospholipids bilayers at 1:3 (LA:Lipid) molar ratio. Simulations for different ionization states of the PLC were able to capture important features of the PLC–phospholipid bilayer interactions. Furthermore, we study the encapsulation of prilocaine, in a small unilamellar liposome [2]. We carried out a series of molecular dynamics simulations using a coarse grain model. We extended the recently developed MARTINI [3] coarse grain model to access relevant time and length scales. Our simulations, for different protonation states of the PLC, captured important features of the PLC-vesicle interactions.   References: