Rani Soni, Behera Manisha, Ghorai Soma Mondal, Singh Gagandeep
Department of Zoology, Hindu College, University of Delhi, Delhi, 110007 India.
Section of Microbiology, Central Ayurveda Research Institute, Jhansi, Uttar Pradesh 284003 India.
In Silico Pharmacol. 2025 Jun 9;13(2):82. doi: 10.1007/s40203-025-00376-8. eCollection 2025.
Anaesthetics such as barbiturates function as inhibitory-neurotransmitters by attaching to the accessible pockets of the GABA receptors, which function through ligand-gated Cl channels. This study investigates the interaction dynamics between various barbiturate analogues and GABA 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 GABA 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 GABA 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.
巴比妥酸盐等麻醉剂通过附着于GABA受体的可及口袋发挥抑制性神经递质的作用，GABA受体通过配体门控氯离子通道发挥功能。本研究调查了各种巴比妥酸盐类似物与GABA受体之间的相互作用动力学，以确定具有改善治疗特性的苯巴比妥潜在替代物。进行了全面的ADME/TOX评估、分子对接研究、分子动力学分析、结合自由能计算以及使用通道注释包的离子通道分析，以检查苯巴比妥、2-硫代巴比妥酸盐和几种螺环巴比妥酸盐衍生物与GABA受体的相互作用。我们的研究结果表明，仅分子对接无法预测调节氯离子转运的治疗效果。尽管螺环巴比妥酸盐表现出强烈的相互作用（特别是甲氧基-SB为-53.20千卡/摩尔，而苯巴比妥为-31.22千卡/摩尔），但它们的药代动力学性质欠佳，分子量超过500克/摩尔，限制了它们的生物利用度。值得注意的是，2-硫代巴比妥酸盐尽管结合亲和力相对较弱（-27.70千卡/摩尔），但仍是最有前景的候选物，因为它与所有GABA受体链表现出稳定的相互作用，具有优异的肠道和血脑屏障通透性、良好的生物利用度以及最小的毒性问题。这些结果挑战了药物发现中优先考虑高结合亲和力的传统方法，并强调了在适度结合与最佳通道功能及有利的ADME/TOX性质之间取得平衡的重要性。2-硫代巴比妥酸盐是苯巴比妥的潜在更安全替代物，苯巴比妥目前被列为滥用药物，为轻度抗抑郁药和催眠药物的开发提供了新的可能性。
