Virtual screening and in vitro evaluation of putative positive allosteric modulators of the GABAB receptor

Abstract

-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system (CNS). GABA exhibits its function by binding to either the ionotropic GABAA receptor or the metabotropic GABAB receptor, causing a decrease in activity in the nervous system. Disruption in the GABAergic system has been associated with various neurological conditions, including Alzheimer’s disease, anxiety, depressive disorders, and epilepsy.

Currently, there is only one marketed drug that work on the GABAB – receptor, on the orthosteric site to be more specific. The discovery of allosteric modulators for the G-protein coupled receptors provides a promising new strategy with potential for developing novel treatments for a variety of CNS disorders, as they allow for increased drug selectivity and potentially decreased adverse side effects.

Homology models of the GABAB receptor were built due to the lack of an experimentally solved three-dimensional structure, and they were used to screen for potentially new allosteric modulators using a combination of structure-based and ligand based virtual screening (in silico) with compounds from the Molport database and DrugBank. 16 compounds were purchased for testing – 8 from each database, and were further investigated and evaluated by experimental in vitro testing.

Our results indicate that we have four hits, two from each database (DrugBank: I-4 = Mefloquine and I-10 = Rivaroxaban, Molport: I-23 and I-24) where it seems like I-4, I-23 and I-24 acts like PAMs whereas I-10 acts like a NAM/antagonist. The compounds from DrugBank, especially Mefloquine is of interest due to its well-known adverse effect profile which may be linked to the GABAergic system. Further investigation and confirmation of activity at the GABAB receptor could potentially lead to development of novel drugs as well as important tools for studying the structure and function of the GABAB receptor. And at the same time be used to explain the side effects seen when using Mefloquine.