K+ Channels and Some Familiar Antiepileptic Drugs: Evaluation of Their the Structure-Activity Relationships with Molecular Docking Analysis

Year 2023, Volume: 10 Issue: 2, 305 - 325, 31.05.2023

Esra Nur Çakmak , Mahmut Gür , Bayram Kıran

https://doi.org/10.31202/ecjse.1213826

Abstract

This study includes the structure-activity relationship of active molecules that are commonly used in the treatment of convulsive seizures in epileptic diseases. Well-known epileptic active molecules studied are: Vigabatrin, Lokosamidine, Zonisamide, Oxcarbazepine, Levetiresetam, Tiagabine, Topiramate, Lamotrigin, Gabapentin, Felbamat, Ethosuximide, Valproic Acid, Mesuximide, Ethotoin, Primidon, Trimethadion, Phenytoin, Remasemide, Mephenytoin. These molecules, which were selected considering the physiopathological mechanisms of action of epileptic disease, were considered suitable for molecular docking studies since they were used as a potential antiepileptic agent. In addition, it was focused on the potassium channels, which were prominent in the mechanisms of epilepsy. During the action potential that triggers seizure formation, inward rectifying potassium channels (KIR3.2) make a important role providing the flow of K+ ions.
Thus, PDB ID: 4KFM receptor was chosen for molecular docking study, since its act as an agonist according to its activity on the canal in the case of epileptic seizures formation. The result of molecular docking analysis demonstrated that Phenytoin gave the best binding affinity for 4KFM with a value of -6.2 kcal/mol. Other analysis in descending order (as kcal/mol); Oxcarbazepine (-6,0), Remasemide (-5.9), Topiramate and Primidon (-5.8), Tiagabine, Felbamat and Mesuximide (-5.7), Lamotrigin (-5.6) Zonisamide, Ethotoin and Mephenytoin, Lokosamidine (-5.5), Gabapentin (-4.8), Trimethadion (-4.7), Ethosuximide (-4.6), Levetiresetam (-4.5), Vigabatrin (-4.0), Valproic Acid (-3.9) determined as.

Keywords

Antiepileptic, Drug, Moleculer Docking, Potassium channel, Epilepsy

References

• [1]. W. Loscher, “Current status and future directions in the pharmacotherapy of epilepsy,” Trends Pharmacol Science, vol. 23, no. 3, pp. 113-118, 2002.
• [2]. A. K. Ngugi, S. M. Kariuki, C. Bottomley, I. Kleinschmidt, J. W. Sander, and C.R. Newton, “Incidence of epilepsy: a systematic review and meta-analysis,” Neurology, vol. 77, no. 10, pp. 1005-1012, 2011.
• [3]. H. E. Scharfman, “The neurobiology of epilepsy,” Current Neurology and Neuroscience Reports, 7(4):348-354, 2007.
• [4]. J. Q. Kang, and R. L. Macdonald, “Making sense of nonsense GABA(A) receptor mutations associated with genetic epilepsies,” Trends in Moleculer Medicine, vol. 15, no. 9, pp. 430-438, 2009.
• [5]. R. Wallace, “Mutations in GABA-receptor genes cause human epilepsy,” The Lancet Neurology, vo. 1, no. 4, pp. 212, 2002.
• [6]. G. Krapivinsky, E. A. Gordon, K. Wickman, B. Velimirovic, L. Krapivinsky, and D. E. Clapham, “The Gprotein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins,” Nature, vol. 374, no. 6518, pp. 135-141, 1995.
• [7]. P. A. Slesinger, E. Reuveny, Y. N. Jan, and L. Y. Jan, “Identification of structural elements involved in G protein gating of the GIRK1 potassium channel,” Neuron, vol. 15, no. 5, pp. 1145-1156, 1995.
• [8]. E. Akyüz, and P. M. Tiber, “İçeri doğrultucu potasyum kanalları ve epilepsi”, Journal of Harran University Medical Faculty, vol. 14, no. 2, pp. 141-149, 2017.
• [9]. P. R. Camfield, C. S. Camfield, K. F. Swaiman, S. Ashwal, and D. M. Ferriero, “Pediatric Epilepsy: Pediatric Neurology Principles & Practice,” Mosby Elsevier, vol. 1, no. 9996004716, pp. 981-989, 2006.
• [10]. C. L. Deckers, P. Genton, G. J. Sills, and D. Schmidt, “Current limitations of antiepileptic drug therapy: a conference review,” Epilepsy Research, vol. 53, pp. 1-17, 2003.
• [11]. C. A. Doupnik, “Identification of aethina tumida kir channels as putative targets of the bee venom peptide tertiapin using structure-based virtual screening methods,” Toxins, vol. 11, no. 546, pp. 1-17, 2009.
• [12]. Y. Zhao, P. Man-UnUng, G. Zahora´nszky-Kohalmi, A. Schlessinger, J. J. Marugan, and P. A. Slesinger, “Identification of a G-protein-ındependent activator of gırk channels,” Cell Reports, vol. 31, no. 11, pp. 1-18, 2020.
• [13]. https://www.rcsb.org/structure/4kfm Date of access 20. 12, 2022.
• [14]. M. R. Whorton, and R. Mackinnon, “X-ray structure of the mammalian GIRK2-beta gamma G-protein complex,” Nature, vol. 498, no. 7453, pp. 190-197, 2013.
• [15]. Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.
• [16]. J. Eberhardt, D. Santos-Martins, A. F. Tillack, and S. Forli, “AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings,” Journal of Chemical Information and Modeling, 2021.
• [17]. O. Trott, and A. J. Olson, “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading,” Journal of Computational Chemistry, vol. 31, pp. 455-461,2010.
• [18]. S. Piplani, V. K. Saini, R. R. Niraj, A. Pushp, and A. Kumar, “Homology Modlling and molecular kenetleme studies of human placental cadherin protein for its role in teratogenic effects of anti-epileptic drugs,” Computational Biology and Chemistry, vol. 60, pp. 1-8, 2016.
• [19]. S. Jamal Gilani, M. Zaheen Hassan, S. Sarim Imam, C. Kala, and S. P. Dixit, “Novel benzothiazole hydrazine carboxamide hybrid scaffolds as potential in vitro GABA-AT enzyme inhibitors: Synthesis, molecular kenetleme and antiepileptic evaluation,” Direct Bioorganic & Medicinal Chemistry Letters, vol. 29, pp. 1825-2830, 2019.
• [20]. N. Shahabadi, A. Khorshidi, and N. M. Moghadam, “Study on the Etkileşim of the epilepsy drug, zonisamide with human serum albumin (HSA) by spectroscopic and molecular docking techniques,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 114, pp. 627-632, 2013.
• [21]. R. K. Prasad Tripathi, and S. R. Ayyannan, “Anticonvulsant activity, organotypic hippocampal neuroprotection assay and in-silico sodium channel blocking potential of 2-amino-6nitrobenzothiazole derived semicarbazones,” Biomedicine & Pharmacotherapy, vol. 95, pp. 1451-1460, 2017.
• [22]. L. Fijalkowski, K. Salat, A. Podkowa, P. Zaręba, and A. Nowaczyk, “Potential role of selected antiepileptics used in neuropathic pain as human GABA transporter isoform 1 (GAT1) inhibitors-Molecular docking and pharmacodynamic studies,” European Journal of Pharmaceutical Sciences, vol. 96, pp. 362-372, 2017.