Molecular Docking and ADMET Profiling of Hydantoin Derivatives Targeting Voltage-Gated Sodium Channel (PDB ID: 1N45) for Epilepsy Treatment

Introduction: Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal neuronal excitability, often associated with dysfunction of voltage-gated sodium channels. The present study aims to design and evaluate novel hydantoin-based derivatives of Phenytoin (PHT) as potential anticonvulsant agents using comprehensive in silico approaches. Materials and Methods: A series of ten derivatives (SB-1 to SB-10) were designed and assessed for their physicochemical properties, pharmacokinetic behavior, drug-likeness, toxicity profile, and molecular docking interactions with the voltage-gated sodium channel protein (PDB ID: 1N45). Results: Physicochemical analysis demonstrated that most compounds possess favorable drug-like characteristics, including optimal lipophilicity and acceptable topological polar surface area, supporting good membrane permeability. ADME predictions revealed high gastrointestinal absorption and blood-brain barrier permeability for selected derivatives, indicating their potential for central nervous system activity. Discussion: Toxicity assessments suggested low cardiotoxicity and minimal clinical toxicity risk, although moderate mutagenicity was observed in a few compounds, necessitating further validation. Molecular docking studies showed strong binding affinities across all derivatives, with docking scores ranging from -7.5 to -9.5 kcal/mol. Among the series, SB-3 exhibited the highest binding affinity, supported by diverse interactions including electrostatic, hydrophobic, and π-mediated interactions, while SB-8 and SB-9 also demonstrated significant binding stability through multiple hydrogen bonds. Conclusion: The integrated computational findings highlight SB-3 as a promising lead compound, with SB-8 and SB-9 as potential candidates for further development. This study provides valuable insights into the rational design of novel anticonvulsant agents targeting sodium channels and establishes a foundation for future experimental validation and optimization.