Zeb Ahmad, Ali Hussain, Khan Jehan Zeb, Shah Fawad Ali, Alattar Abdullah, Alanazi Fawaz E
Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad Pakistan.
Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia.
PLoS One. 2025 Jun 20;20(6):e0325772. doi: 10.1371/journal.pone.0325772. eCollection 2025.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, affecting millions of people worldwide. Phenytoin is a widely used antiepileptic drug, but its therapeutic efficacy is limited by poor brain penetration and undesirable side effects. We have investigated the drug against the selected candidate's protein target using Insilco analysis to check the mode of action in real time system. This makes Phenytoin a promising therapeutic drug for the management of different targets involved in Epilepsy disease. Considering this, using a wide range of computer aided drug-designing approaches, high interactions with the protein targets have been inferred against drug molecule Phenytoin. Eight receptors against Phenytoin molecules showed binding interactions during molecular docking but the top four i.e. Bcl-2, BDNF, IL-1β and Caspase showed high binding affinities with docking score of 7.8 kcal/mol, 7.7. kcal/mol. 7.4 kcal/mol and 7.1 kcal/mol respectively. The compound Phenytoin interacts with several important active side residues in the active domain of all the receptors which was further validated via molecular dynamic simulations for 100 ns time intervals. Furthermore, the complexes of Phenytoin reveal very stable dynamics with average RMSD, RMSF and ROG values with stable carbon-alpha atoms confirmation at different intervals. In conclusion, these molecules are promising and require experimental validation to prove them as epilepsy inhibitors.
癫痫是一种慢性神经疾病,其特征为反复发作的癫痫,全球数百万人受其影响。苯妥英是一种广泛使用的抗癫痫药物,但其治疗效果受到脑渗透率低和不良副作用的限制。我们使用计算机模拟分析针对选定候选蛋白靶点研究了该药物,以实时系统检查其作用模式。这使得苯妥英成为一种有望用于治疗癫痫疾病中不同靶点的治疗药物。考虑到这一点,使用多种计算机辅助药物设计方法,已推断出药物分子苯妥英与蛋白靶点具有高度相互作用。在分子对接过程中,针对苯妥英分子的八种受体显示出结合相互作用,但排名前四位的即Bcl-2、脑源性神经营养因子(BDNF)、白细胞介素-1β(IL-1β)和半胱天冬酶显示出高结合亲和力,对接分数分别为7.8千卡/摩尔、7.7千卡/摩尔、7.4千卡/摩尔和
7.1千卡/摩尔。化合物苯妥英与所有受体活性域中的几个重要活性侧链残基相互作用,这通过100纳秒时间间隔的分子动力学模拟得到进一步验证。此外,苯妥英的复合物显示出非常稳定的动力学,具有平均均方根偏差(RMSD)、均方根波动(RMSF)和回转半径(ROG)值,在不同时间间隔有稳定的碳α原子确认。总之,这些分子很有前景,需要进行实验验证以证明它们是癫痫抑制剂。