In silico screening for GAT-3 inhibitors

Abstract

ϒ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the central nervous system (CNS). GABA exert is function by binding to three different receptor subtypes, the GABAA, GABAB and GABAC receptor. The GABA level in different brain regions are regulated by four GABA transporters (GATs); GAT-1, GAT-2, GAT-3 and BGT-1. GAT-3 is located in glial cells that is controlling GABA function in the synapses. A study has shown that Alzheimer’s disease (AD) patients have an elevated GABA levels in the cerebrospinal fluid, while a transgenic mouse model of AD showed an unusual high GABA content in dentate gyrus (DG) and enhanced inhibition. The high GABA content in DG is a result of transport by the GABA transporter, GAT-3, and it is suggested that GAT-3 inhibitors may be a novel therapy. AD is the most common form of dementia, and is a worldwide disease with increasing incidence with age. There is no treatment that can cure the AD today and GAT-3 inhibitors may represent a new direction in the search for new therapeutic strategies.

The three dimensional (3D) structure of GAT-3 is unsolved. Therefore, X-ray structures of the drosophilia dopamine transporter (dDAT) and the human serotonin transporter (hSERT) were used to construct homology models of GAT-3. The homology models were evaluated by docking a set of known inhibitors, substrates and decoys, and the best performing models were used in combined ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) in order to identify potential GAT-3 inhibitors compounds from the ENAMINE database.

Four homology models were selected based on their ability to separate binders from non-binders by BEDROC calculation. 40 hit compounds from ENAMINE were selected with good docking score that may be potential GAT-3 inhibitors drug candidates. These hit compounds need evaluation by experimental testing.