Integrated Virtual Screening and Molecular Dynamics Simulation Study to Discover Potential Activators of γ‐Aminobutyric Acid B Receptor 1 for Therapeutic Targeting of Neurodegenerative Diseases

Neurodegenerative disorders are characterized by imbalances in synaptic signaling, often driven by dysregulation of the γ-aminobutyric acid B receptor 1 (GABBR1). Its dysregulation has been identified as a key pathophysiological mechanism contributing to the synaptic failure and neural network instability observed in major neurodegenerative disorders. Therapeutic strategies that target GABBR1 activation offer a promising approach to restoring excitatory-inhibitory homeostasis in the central nervous system. This study employed an integrated computational workflow to identify potent GABBR1 modulators by repurposing an FDA-approved drug library. Structure-based virtual screening, PASS analysis, and binding site interaction analysis identified Cinacalcet and Trifluperidol as top candidates, exhibiting binding affinities of -10.2 and -9.0 kcal/mol, respectively, which are higher than that of the reference antagonist (-6.0 kcal/mol). Density functional theory calculations confirmed the favorable electronic properties and reactivity for both compounds. The molecular dynamics (MD) simulations of 500 ns validated the structural stability of GBARR1-ligand complexes, revealing that Cinacalcet induces a compact, rigid GABBR1 conformation. MM/PBSA analysis demonstrated robust binding free energies of -21.50 kcal/mol for Cinacalcet and -13.13 kcal/mol for Trifluperidol. These findings suggest that Cinacalcet and Trifluperidol are promising candidates for drug repurposing in the treatment of neurodegenerative diseases caused by the dysregulation of GABBR1. This study contributes to public health research and aligns with Sustainable Development Goal 3 (Good Health and Well-being) by supporting the development of novel therapeutic strategies for neurodegenerative diseases.