Introduction: Gamma-aminobutyric acid type A (GABAA) receptors play a crucial role in facilitating rapid synaptic inhibition within the brain. Recent advancements in technology have greatly improved our understanding of the distinct roles played by various GABAA receptor subunit classes and isoforms in normal brain function. Clinical drugs and general anesthetics target numerous GABAA receptors, with each combination of receptors mediating distinct physiological functions. Cannabidiol (CBD), a non-intoxicating component of cannabis, possesses anti-epileptic and anti-hyperalgesic properties. While some endogenous and synthetic cannabinoids interact with GABAA receptors, the mechanism of action of CBD requires further investigation .CBD, one of two main cannabinoids found in the cannabis plant, has various functional effects and can alleviate psychotic symptoms. Evidence suggests that CBD act as a positive allosteric modulator for all GABAA receptors containing α subunits.
Methods: Molecular docking was performed using AutoDock Tools to assess the binding affinity of the ligand CBD with the GABA receptor, demonstrating the ligand's ability to localize within GABA. The calculation of binding free energies and inhibition constants for the best-docked complex of the ligands and the protein was carried out using AutoDock 4.2. The protein's structure was initially determined using https://blast.ncbi.nlm.nih.gov, and the three-dimensional crystal structure of the protein was obtained through the website http://www.rcsb.org. Ligands were prepared by downloading their chemical composition in SDF format from https://pubchem.ncbi.nlm.nih.gov. Subsequently, their PDB structures were obtained and saved using http://www.cheminfo.org/Chemistry/Cheminformatics/FormatConverter/index.html.
Results: Molecular docking revealed the binding affinity of cannabinol (CBN) and cannabidiol (CBD) to the alpha 1 subunit of the GABA1 receptor, which is a key inhibitory neurotransmitter receptor in the mammalian brain. The results indicate that both cannabidiol (CBD) and cannabinol (CBN) have the potential to form complexes with the GABA receptor. The binding free energy for CBN is -4.87 kcal/mol, which is more negative than that for CBD (-4.27 kcal/mol), suggesting stronger binding for CBN. Additionally, the inhibitory constant (Ki) for CBN is smaller than that for CBD, indicating that CBN possesses greater inhibitory potential. Consequently, CBN, with its more negative binding free energy and smaller Ki, is deemed a more suitable ligand for the GABA1 receptor.
Conclusion: The field of molecular docking, with its computational ability, has emerged as a powerful tool in predicting drug candidates for various diseases. This research has shed light on the significance of GABAA receptors in the central nervous system and their implications in neuropsychiatric disorders. GABAA receptors, with their diverse subunit compositions and roles, are key players in maintaining neural communication and homeostasis. Their modulation by compounds like cannabidiol (CBD) raises intriguing questions about the mechanisms underlying their therapeutic effects. As the understanding of GABAA receptors and cannabinoids deepens, new avenues for drug discovery and the treatment of neurological and psychiatric disorders may emerge