Investigation of structure-activity relationships with molecular docking for some antiepileptic drugs and voltage-gated calcium (CaV) channels

Öz

In the study, the active drugs molecules used in the treatment of convulsive seizures occurring in epilepsy disease were used. These molecules; Vigabatrin, Lokosamidin, Zonisamide, Oxcarbazepine, Levetiracetam, Tiagabin, Topiramate, Lamotrigine, Gabapentin, Felbamate, Ethosuximide, Valproic Acid, Mesuximide, Ethotoin, Primidone, Trimethadion, Phenytoin, Remasemide, Mephenytoin. These molecules have been selected considering the physiopathological mechanisms of action of epilepsy. Since the selected molecules are used as a potential antiepileptic agent, they were deemed suitable for molecular insertion studies. In addition, voltage-gated calcium channels, which play an important role in epilepsy, are emphasized. Voltage-gated calcium channels (CaV) act by providing the flow of Ca+ ions during the action potential that triggers seizure formation, and among the ten subtypes of voltage-gated calcium (CaV) channels, CaV3.1- CaV3.3, T-type or abnormal activities are associated with epilepsy, psychiatric form the associated low-voltage-activated subfamily. For this reason, the PDB ID: 6KZP receptor, which acts as an antagonist according to its activity on the channel in the formation of epileptic seizures, was chosen for the molecular insertion study. As a result of molecular placement studies; Oxcarbazepine and Phenytoin gave the best binding affinity for 6KZP with a value of -7.5 kcal/mol. Other results are in descending order (in kcal/mol); Tiagabine (-7.4), Mesuximide (-7.3), Primidone (-7.1), Remacemide (-7.0), Topiramate (-6.9) Mephenytoin (-6.7), Lomotrigine and Ethotoin (-6.4), Locosamide and Zonisamide (-6.1) , Felbamate (-6.0), Levetiracetam and Gabapentin (-5.4), Esuximide (-5.1), Valproic Acid (-4.9), Trimethadione (-4.7), Vigabatrin (-4.4) determined as.

Anahtar Kelimeler

• Calcium Channels
• Epilepsy
• Moleculer Docking
• Ligand
• Receptor
• Drug

Kaynakça

1. Adams, R.D., Victor, M. and Ropper, A.H., (2001). Epilepsy and Other Seizure Disorder. Principles of Neurology, Seventh ed, New York: McGrawHill; 331-365.
2. Fisher, R.S., Boas, W.V.E., Blume, W., Elger, C., Genton, P., Lee, P. and Engel, J., (2005). Epileptic Seizures and Epilepsy: Definitions Proposed By The International League Against Epilepsy (ILAE) And The International Bureau For Epilepsy (IBE). Epilepsia, 46; 470-472.
3. Scharfman, H.E., (2007). The Neurobiology of Epilepsy. Current Neurology and Neuroscience Reports,7(4);348-54.
4. Yılmaz, M., (2008). Ratlarda Pentilentetrazol Ile Oluşturulan Epileptik Nöbet Modelinde Topiramatın Beyin Kalsiyum, Ca+2atpaz Ve NMDA Reseptörleri Üzerine Etkileri. Uzmanlık tezi, Süleyman Demirel Üniversitesi Tıp Fakültesi Nöroloji Anabilim Dalı, Isparta.
5. Sarı, S., (2018). (Arilalkil)Azol Yapısında Yeni Oksim Ester Türevleri Üzerinde Çalışmalar: Sentez, Biyolojik Aktivite Ve Moleküler Modlleme. Doktora Tezi, Hacettepe Üniversitesi Sağlık Bilimleri Enstitüsü, Ankara.
6. Kandel, E.R., Schwartz, J.H. and Jessell, T.M., (2000). Principles of Neural Science. 4th ed. New York: McGraw-hill.
7. Fattore, C. and Perucca, E., (2011). Novel Medications for Epilepsy. Drugs, 71; 2151– 2178.
8. Loscher, W., (2011). Critical Review of Current Animal Modls of Seizures And Epilepsy Used In The Discovery And Development Of New Antiepileptic Drugs. Seizure. 20; 359–368.

9. Edafiogho, I.O., Ananthalakshmi, K.V. and Kombian, S.B., (2006). Anticonvulsant Evaluation and Mechanism of Action of Benzylamino Enaminones. Bioorganic & Medicinal Chemistry, 14:5266-72.
10. Malik, S., Bahare, R.S. and Khan, S.A., (2013). Design, Synthesis and Anticonvulsant Evaluation of N-(Benzo[D]Thiazol-2-Ylcarbamoyl)-2- Methyl-4-Oxoquinazoline-3(4H)- Carbothioamide Derivatives: A Hybrid Pharmacophore Approach. European Journal of Medicinal Chemistry, 67:1-13.
11. Christian, E. and Schmidt, D., (2008). Modern Management of Epilepsy: A Practical Approach. Epilepsy & Behavior, 12(4):501-539.
12. Duncan, J.S., Sander, J.W., Sisodiya, S.M. and Walker, M.C., (2006). Adult Epilepsy. Lancet Neurology, 367:1087-1100.
13. Onat, F. and Eşkazan, E., (2008). Bora İ, Yeni SN, Gürses C (editörler). Epilepsi. İstanbul: Nobel Matbaacılık, s595– 607.
14. Bechi, E., (2004). Efficacy and Tolerability of The New Antiepileptic Drugs: Comparison Of Two Recent Guidelines. Lancet Neurology, 3:618-621.
15. Crumrine, P.K., (2002). Antiepileptic Drug Selection in Pediatric Epilepsy. Journal of Child Neurology, 17 Suppl 2:2S-S8.
16. Chen, Y., Parker, W.D. and Wang, K., (2014). The Role of T-Type Calcium Channel Genes in Absence Seizures, Frontiers in Neurology, 5:45.
17. Hacımüftüoğlu, A., (2007). Nörotoksisite Ve Glutamat İlişkisi. Trabzon Sunumu, Atatürk Üniversitesi, Famokoloji, Ankara. s(38).
18. Piplani, S., Saini, V., Niraj, R. R. K., Pushp, A. and Kumar, A., (2016). Homology modelling and molecular docking studies of human placental cadherin protein for its role in teratogenic effects of anti-epileptic drugs. Computational Biology and Chemistry, 60, 1–8. doi:10.1016/j.compbiolchem.2015.11.003
19. Kundaikar, H. S., Sancheti, J. S., Jain, P. D., Degani, M, S. and Sathaye, S., (2015). Docking studies and pharmacological evaluation of antiepileptic activity of phytoconstituents. Medicinal Chemistry Research, 24(8), 3296–3304. doi:10.1007/s00044-015-1377-x
20. Available: https://pubchem.ncbi.nlm.nih.gov/, Accessed on; Feb.02,2020
21. Available: https://www.rcsb.org/search, Accessed on; Feb.02,2020
22. Dassault Systèmes BIOVIA, Discovery Studio Modlleme Ortamı, Sürüm 2017, San Diego: Dassault Systèmes, 2016.