Multiscale Study of Sumatriptan in Model Membranes

I. WOOD; M. PICKHOLZ

Maresias

Workshop; II Workshop on Biomolecular-Theory Experiment Interplay; 2015

II WBioTEI

Motivation: Sumatriptan (SMT) is an antimigraine drug, specially designed as serotonin receptor agonist. SMT has a low partition coefficient. This fact could prevent the drug to reach the central nervous system at clinical effective concentrations through crossing process through blood-brain barrier. In this direction, computer simulations were used in order to reveal, at the molecular level, their intewractions and the effects of copolymers in model barriers in the presence of sumatriptan. Furthermore, in order to improve the sumatriptan efficacy, it was proposed their incorporation in poloxamer micelles is being proposed. Methods: Molecular Dynamics (MD) simulations were carried out through two different strategies: i) Atomistic MD simulations of sumatriptan in model membranes as function of its concentration and the pH of the system. ii) Coarse grain (CG) MD approach (within the MARTINI force field [1]). In this second approach firstly we have reproduce the results of atomistic MD to refine the parameters of a SMT CG model. Within this model we have advanced to understand more complex systems, like the SMT encapsulation in poloxamer micelles and the effects of poloxamer unimers in the SMT permeation through the lipid bilayers.Results: SMT is an indole derivative, as well as the aminoacid tryptophan, it shows an interfacial localization preference in model membranes. Preliminar RMN results confirm this localization [2]. The main specific interactions between SMT and lipid head groups are cation-, salt bridges and hydrogen bonds. The strength of the interactions depends on the concentration. For instance, cation- and salt bridges per molecule decrease with concentration. It was proposed in the literature that the F127 unimer (one of the more used poloxamers) interaction with membranes could alter their organization, helping the passive diffusion of drugs. We have found that F127 adopts a transmembrane or a U-shape conformation within the membrane, exposing the entire PPO block along the bilayer thickness (since terminals methyl to glycerol groups) and leaving PEO blocks free toward aqueous phase. In this way, we have investigated how the interaction of SMT with membranes is affected by the presence of F127. Even if changes were observed, SMT was unable to cross from one monolayer to the other. By the other hand, we investigate the encapsulation of SMT in F127 micelle. We found that SMT originally placed in water diffuses into the micelle and essentially partition in its hydrophilic crown, as shown in Fig.1. [1] Marrink, S., e.t al, J. Phys. Chem. B, 2007, 111, 7812. [2] Structural and Dynamical Evidences of Triptan Partition and Interaction in Model Membranes: Combining Simulations and NMR, I. Wood, K. Seremeta, L. Fabián, D. R. de Araujo, L.F. Cabeça, E. de Paula, Mónica Pickholz, International Conference of Bioscience of Lipids 2015.Support: CONICET, MINCyT y U.B.A.