Using Virtual Screening for the discovery of new GABAergic insecticides: assessment of Rdl homology models and docking scoring functions

IVÁN FELSZTYNA; MIGUEL V; VILLARREAL MA; DANIEL A. GARCÍA

Congreso; Congreso Anual de la Sociedad Argentina de Biofísica; 2019

Insectnervous system is the main target of the most used insecticides, as is the caseof non-competitive antagonists (NCAs) that block GABAA receptor(GABAA-R). In insects, the homopentamer formed by the so-called Rdlsubunit is the most representative type of GABAA-R. Docking basedvirtual screening is a computational method that allows to explore libraries ofchemical compounds in order to identify those which are most likely to bind toa protein target. We aim to validate Rdl structural models and scoring functionsto carry out a virtual screening of NCAs that bind to Aedes aegypti Rdl homopentamer (Rdlhomo5). Since thereare no experimental 3D structures of any insect Rdlhomo5, we performedhomology modelling  to obtain our proteinstructure. GABAA-R, as well as the rest of Cys-loop receptors, is atransmembrane ion channel whose conformation varies among three pharmacologicalstates: open, closed and desensitized. Considering that the NCAs binding siteis located inside the channel pore, and its conformation could affect the dockingcalculation of the binding of these ligands, we obtained homology models basedon Cys-loop receptors templates in the three pharmacological states. A set ofligands which are known to act as GABAA-R NCAs were docked in theproposed binding site of all our models, and the binding energy obtained bydocking was compared with experimental data for each of the compounds. Also, wereused  different docking scoringfunctions, in order to select the combination of protein structure and scoringfunction that results in the best correlation with the experimental data. Althoughin previous NCAs binding studies an open channel template was chose to model aninsect Rdlhomo5, we obtained the best correlation to experimentaldata using a model based on a structure crystalized in the desensitized state(human GABAA-R β3 homopentamer), using the Vinardo scoring function. Afterwards, this scoringfunction was tuned in order to improve the obtained correlation coefficient.