EXPLORING GABA AS A DRUG TARGET: MOLECULAR DOCKING ANALYSIS FOR ALZHEIMER’S DISEASE DRUG REPURPOSING

Abstract

: Alzheimer's disease (AD) is a long-term, irreversible brain condition characterized by behavioral abnormalities, memory loss, and cognitive decline. A major pathological characteristic of AD is abnormal accumulation of Aβ plaques, resulting from the improper breaking of APP. Among the critical enzymes involved in APP processing, Because of its influence on cognitive processes and the balance of excitatory and inhibitory neurotransmission, GABA (γ-aminobutyric acid) is becoming more and more important in Alzheimer's disease (AD). Since all currently licensed therapeutic medications for AD are cholinergic and glutamatergic system modulators and have only modest effects, it appears that additional pharmacological targets are required to restore the E/I imbalance. Research suggests that changes in GABAergic signaling may be a therapeutic target for AD since they are linked to the cognitive impairment seen in the disease. The present study focused on identifying potential modulators of GABA receptor in AD, through a molecular docking-based drug repurposing approach. Drugs structurally similar with Clonazepam, a known inducer of GABA identified using computational screening tools. To develop more effective treatment strategies for Alzheimer's disease, the study intends to use molecular docking to find alternative or repurposed therapeutics that might offer better binding affinity and possibly better therapeutic outcomes than donepezil. Results: Docking simulations revealed that several compounds demonstrated higher binding affinities compared to Clonazepam, indicating stronger potential interactions with Alpha chain of GABA active site. Notably, several drugs exhibited higher binding affinities than Clonazepam, suggesting stronger and potentially more effective interactions with GABA A. Among these, Temazepam, Oxazepam , Prazepam and Nitrazepam emerged as the most promising candidates, 2 demonstrating superior docking scores and favorable interaction profiles. Further, 2D interaction analysis was carried out using BIOVIA Discovery Studio, which visually illustrated key binding interactions such π–π stacking, hydrophobic interactions, and hydrogen bonding between the ligands and critical amino acid residues of the GABA A protein followed by a toxicity assessment using ProTox II server.