Molecular Docking Mediated Virtual Drug Screening for GABAA Receptor: Promising Digoxin Derivatives

Abstract

In the central nervous system (CNS) of mammalian species, ℽ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter due to it regulates neuronal development through leading neural differentiation, proliferation, migration, etc. GABAA receptor is the major GABA receptor since it has the highest expression level among the other GABA receptors within CNS. Many pieces of evidence prove that the defects in the GABAergic pathway might give rise to serious diseases such as schizophrenia, epilepsy, anxiety, depression, insomnia, etc. In this study drug library with a totally of 8170 ligands consists of three distinct datasets which are FDA-approved Drugs, Drugs Approved by World but not FDA, and Non-human Metabolites have been screened for the allosteric site of the GABAA receptor with PyRx Virtual Screening Tool and ligand-receptor interactions have been analyzed with Biovia Discovery Studio software. Results reveal that Digoxin and its two distinct derivatives (DD1 and DD2), as well as Conivaptan, are promising in the treatment of GABAergic pathway-based disorders. The findings of this report should be verified with further molecular dynamics (MD) simulations and the ligands should be tested by both in vitro and in vivo studies.