Molecular Dynamic Simulation of Sumatriptan in Model Lipid Bilayers: Localization and Drug-Lipid Interactions

I. WOOD; M PICKHOLZ

Salta

Congreso; VIII Congreso Ibero-Americano en Ciencia y Tecnología de Membranas; 2012

CITEM

Abstract Migraine is a neurological disorder which leads to recurring, unilateral, throbbing headache, associated with variable incidence of aura (i.e., visual, sensory and motor function disturbances), nausea and vomiting, photophobia and phonophobia, fatigue, and enhanced irritability. In recent years, the role of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) disbalance in pathophysiology of migraine is being extensively studied [1]. The triptans are a new family of drugs designed based on serotonin (5-HT) structure. There are seven triptans available in market, at different dosages and formulations. All of triptan analogous share the same basic structure with 5-HT, indole, and the same positions of indole ring substituents (see Fig.1). The triptans mainly acts on 3 subtypes of serotonin receptors (5- HT1B, 5-HT1D and 5-HT1F) agonists. The triptans have different physichal-chemical properties -such as lipophilicity-, pharmacokinetics -such as absorption and distribution- and ability to cross blood-brain barrier (BBB). Among them, the prototype sumatriptan (SMT), was the first triptan developed and is the most widely distributed. Sumatriptan has a low lipophilicity, characterized by a low partition coefficient between membrane and water, such difficult the cross process through BBB [2]. In this way, understanding of the interaction triptans with biological membranes could provide insights on the anesthesia mechanism could help, for instance, to improve their efficacy. Nowadays, intensive research is focused in drug entrapped into drug delivery systems to enhance their activity and pharmacokinetic properties. One strategy for the delivery of triptans could be the encapsulation in liposomes [3]. In this way, the goal of the present work is identify the main interactions between SMT and phospholipids bilayers in order to improve the appropriate drug delivery system for this kind of drugs. Computer simulations are a very powerfull tool to shed light on these interactions. Sumatriptan has a pKA of 9.63 [4], in this way at physiological pH is essentially found at its protonated state. We carried out Molecular Dynamic simulations (MDs) of SMT and 5-HT in model lipid membranes. MDs were performed within the NPT ensemble (constant pressure 1atm and a temperature of 310K). The simulated bilayer consists in 150 1-palmitoil-2-oleoil-sn-glicero-3- phosphatidyl-choline (POPC) phospholipids (75 in each monolayer) and 4200 water molecules. In a first place we study 2 SMT and 2 serotonin molecules in order to compare their localization and main interactions within the membrane. Furthermore we study the concentration effects of SMT molecules in the POPC lipid bilayer. Each simulation was run up 100 ns. Here we study the location, orientation and main interactions between SMT/5-HT molecules and the POPC model membranes by statistical analysis of the MD trajectories. From the electron density profiles, we found that both, SMT and 5-HT molecules, are found essentially at water-lipid head interface. The main interactions between these molecules and lipid bilayer were identified: from the analysis of the radial distribution function we found that pairs of atoms H indole NH group (guest molecule) and O carbonile group (POPC) shows a well defined peak near to 1.7 Å, characteristic distance of hydrogen bond. Taken another pair, the centroid of indole sixmembered aromatic ring (guest molecule) and charged head -N(CH3)3+ choline (POPC), we found a well defined peak near to 4 Å, characteristic of cation-
interaction. Besides, we did not find any crossing events of SMT, even at high molecules concentrations. In this way, we conclude that other strategies should be followed in order to encapsulate a drug into the liposomes, like the use of anionic phospholipid. However, the efficiency could be improved with other drug delivery systems such as polymeric micelles. References [1] P. Humphrey, W. Feniuk, M. Perren, I. Beresford, M. Skingle, E. Whalley. Serotonin and Migraine, Annals New York Academy of Sciences 600 (1990) 587-598. [2] P. Tfelt-Hansen. Does sumatriptan cross the blood–brain barrier in animals and man?, J Headache Pain 11 (2010) 5–12 [3] S. Villasmil-Sánchez, W. Drhimeur, S.C. Salas Ospino, A.M. Rabasco Alvarez and M.L. González-Rodríguez. Positively and negatively charged liposomes as carriers for transdermal delivery of sumatriptan: in vitro characterization 36 (2010) 666-675. [4] GlaxoSmithKlineInc. Imitrex Product Monograph. 2009 Acknowledgments UBA, CONICET and ANPCyT