A COMPUTATIONAL STUDY OF THE BINDING MODES OF LIGANDS AT BENZODIAZEPINES? BINDING SITE ON GABA A RECEPTORS

ANA MARÍA FERREIRA; AMUNDARAIN, MARÍA JULIA; FERNANDO ZAMARREÑO; ALEJANDRO GIORGETTI; MARCELO D. COSTABEL

Ciudad Autonoma de Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; XLVI Reunión Anual de la Sociedad Argentina de Biofísica; 2017

SAB-SAB-SAIC-SAIB-SAI-SAA-SAFE-SAFIS-SAH-SAP

The GABA A Rs, g-Aminobutyric acid type A receptors, belong to thefamily of pentameric ligand gated ion channels and are the main me-diators of fast inhibitory transmission in the mammalian CNS. Theyare the target of a variety of compounds such as GABA, benzodiaz-epines (BZDs), anaesthetics, β-carbolines and neurosteroids, andhave a fundamental role in neurological health.In this work we aim to elucidate the binding modes of relevantligands of the BZDs? binding site, which include classical BZDs, im-idazo-BZDs, zolpidem and eszopiclone. We applied computation-al biophysics methods, namely molecular docking and moleculardynamics (MD) simulations, to undertake this study. We employeda previously developed homology model of the a1β2g2 subtype(based on a β3 homopentamer as a template, PDBID: 4COF) in aclosed desensitized state.We approached molecular docking through different methods:we used HADDOCK which introduces experimental data as ambig-uous interaction restraints and AutoDock Vina which runs a localoptimization from random starting conformations. While the highestranked binding modes were not necessarily the best predictions,some of the docking poses obtained could be related to the exper-imental data.In order to assess the stability of the complexes, we performed100ns MD simulations of the systems with GROMACS (using gro-mos53a6 force field and SPC water model). The receptor was em-bedded in a POPC membrane. RMSD calculations of the backboneshow that the receptors did not suffer major global changes, al-though the presence of the ligands and relaxation of the side chainscaused local modifications.With the aid of experimental information we could predict the bind-ing modes for ligands of the BZDs? site in GABA A Rs. These com-pounds remained bound in the cavity during all MD simulations andimproved their contacts with the receptor. Taking these results intoaccount, we can confirm that our model can be used for further in-vestigation of ligand binding.