Investigation of cannabidiol's potential targets in limbic seizures. In-silico approach

Even though the vast armamentarium of FDA-approved antiepileptic drugs is currently available, over one-third of patients do not respond to medication, which arises a need for alternative medicine. In clinical and preclinical studies, various investigations have shown the advantage of specific plant-based cannabidiol (CBD) products in treating certain groups of people with limbic epilepsy who have failed to respond to conventional therapies. This work aims to investigate possible mechanisms by which CBD possesses its anticonvulsant properties. Molecular targets for CBD's treatment of limbic epilepsy, including hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), gamma-aminobutyric acid aminotransferase (GABA-AT), and gamma-aminobutyric acid type A receptor (GABA_A), were used to evaluate its binding affinity. Interactions with the CB1 receptor were initially modeled as a benchmark, which further proved the efficiency of proposed here approach. Considering the successful benchmark, we further used the same concept for in silico investigation, targeting proteins of interest. As a result of molecular docking, molecular mechanics, and molecular dynamics simulations models of CBD-receptor complexes were proposed and evaluated. While CBD possessed decently high affinity and stability within the binding pockets of GABA-AT and some binding sites of GABA_A, the most effective binding was observed in the CBD complex with HCN1 receptor. 100 ns molecular dynamics simulation revealed that CBD binds the open pore of HCN1 receptor, forming a similar pattern of interactions as potent Lamotrigine. Therefore, we can propose that HCN1 can serve as a most potent target for cannabinoid antiepileptic treatment. Communicated by Ramaswamy H. Sarma.