Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations

FELSZTYNA, IVÁN; GASTALDI, MS; VILLARREAL, MA; GARCÍA, DANIEL A.; MIGUEL, VIRGINIA

Congreso; Primeras jornadas virtuales SAB; 2020

Sociedad Argentina de Biofísica

nsect nervous system is the main target for the most used insecticides, as is the case ofGABAA receptor (GABAA-R) non-competitive antagonists (NCAs). In insects, thehomopentamer formed by the Rdl subunit (Rdlhomo5) is the most representative type ofGABAA-R. Rdlhomo5 presents several binding sites for NCAs. The NCA-IA site is locatedinside the channel pore and is targeted by polychlorocycloalkanes, cyclodienes andphenylpyrazoles. Also, a NCA-II site is located in the transmembrane domains interfacesand is targeted by fluralaner. Since there are no experimental 3D structures of any insectRdlhomo5, in a previous work we performed homology modelling of Aedes aegyptiRdlhomo5 using templates in different pharmacological states. We aim to validatestructural models suitable for performing virtual screening of new NCAs. We have nowevaluated ten different Rdlhomo5 homology models by a retrospective virtual screening. Aset of active ligands for the NCA-I site and a set of property-matched decoys weresubjected to molecular docking. Virtual screening performance in these models wasevaluated by the calculation of ROC curves and ligand enrichment factors. The modelwith the best performance was embedded in a POPC bilayer and subjected to ̴200 nsmolecular dynamics simulations, both in the apo state and in complex with fipronil, aNCA-I site binder insecticide. The protein showed small RMSD values in both states,indicating the structure stability of the homology model. Also, the key interactionsbetween fipronil and the Rdlhomo5 remained stable through the entire MD simulationtime. We are currently evaluating the Rdlhomo5 models in regards to their performance formolecular docking in the NCA-II site. Our results show that several models based ondifferent templates must be evaluated to obtain a trustworthy structure for theapplication of structure-based virtual screening in insect GABAA-R homology models.Contact: ivanfelsztyna@gmail.com