A comprehensive In-silico analysis of the known and novel synthesized 5-substituted barbituric acid derivatives acting as CNS depressants.

Anaesthetics such as barbiturates function as inhibitory-neurotransmitters by attaching to the accessible pockets of the GABAA receptors, which function through ligand-gated Cl- channels. This study investigates the interaction dynamics between various barbiturate analogues and GABAA receptors to identify potential alternatives to phenobarbital with improved therapeutic profiles. The comprehensive ADME/TOX assessments, molecular docking studies, molecular dynamic analysis, binding free energy calculations, and Ion Channel Analysis using Channel Annotation Package were performed to examine the interaction of phenobarbital, 2-thiobarbiturate, and several spirobarbiturate derivatives with GABAA receptors. Our findings reveal that molecular docking alone does not predict therapeutic efficacy in modulating chloride transport. Although spirobarbiturates demonstrated strong interactions (particularly methoxy-SB at - 53.20 kcal/mol compared to phenobarbital's - 31.22 kcal/mol), they exhibited suboptimal pharmacokinetic properties, with molecular weights exceeding 500 g/mol, limiting their bioavailability. Notably, 2-thiobarbiturate emerged as the most promising candidate despite its relatively weaker binding affinity (- 27.70 kcal/mol), as it demonstrated stable interactions with all GABAA receptor chains, superior intestinal and blood-brain barrier permeability, excellent bioavailability, and minimal toxicity concerns. These results challenge the conventional approach of prioritizing high binding affinity in drug discovery and highlight the importance of balancing moderate binding with optimal channel functionality and favourable ADME/TOX properties. 2-Thiobarbiturate represents a potentially safer alternative to phenobarbital, which is currently classified as a drug of abuse, offering new possibilities for the development of mild antidepressants and hypnotic medications.