Molecular Docking Studies on Anticonvulsant Enaminones Inhibiting Voltage-Gated Sodium Channels

Abstract

Epilepsy is described as the most common chronic brain disorder. A typical symptom of epilepsy results in uncontrolled convulsions caused by temporary excessive neuronal discharges. Although several new anticonvulsants have been introduced, some types of seizures have still not been adequately controlled with these new and current therapies. There is an urgent need to develop new anticonvulsant drugs to control the many different types of seizures. Many studies have shown that the epilepsies involve more than one mechanism and therefore may be responsible for the various types of observed seizures. Recently reported studies have shown that a group of newly synthesized 6 Hz active anticonvulsant fluorinated N-benzamide enaminones exhibited selective inhibitions of voltage-gated sodium (Na v ) channels. Na v channels are responsible for the initial inward currents during the depolarization phases of the action potential in excitable cells. The activation and opening of Na v channels result in the initial phases of action potentials. We hypothesize that there is an essential pharmacophore model for the interactions between these enaminones and the active sites of Na v channels. The research reported here is focused on molecular docking studies of the interactions that occur between the fluorinated N-benzamide enaminones and the Na v channels. These studies may open an avenue for designing anticonvulsant drugs by inhibiting Na v channels.

Synthesis, Theoretical Study, and Anticonvulsant Evaluation of N‐Arylenaminones

“…[45,46] On the other hand, the work of other researchers suggests that the most likely mechanism of action is the blockage of the voltage-gated Na + channels (VGSC), as has been demonstrated by electrophysiology experiments and by molecular docking studies carried out on enaminones. [47][48][49][50] The suggested hypothesis for the binding of enaminones to VGSC, matches the pharmacophore proposed for enaminones [51,52] and the general pharmacophore corresponding to the VGSC. Thus, the open-chain N-arylenaminones (3 a-d) can be considered as related to polysubstituted ureas [51,52] (Figure 8).…”

ABORDAGEM IN SILICO COMO FERRAMENTA BIOFÍSICA PARA ESTUDAR A INTERAÇÃO ENTRE FÁRMACOS E CANAIS DE SÓDIO DEPENDENTES DE VOLTAGEM (NaV) ASSOCIADOS À EPILEPSIA

“…Nos resultados de SHAHEEN et al (2015), MINASSIAN et al (2013), FANG et al (2019, PALESTRO et al (2018) e TANG et al (2018, foi possível observar diferentes interações entre os aminoácidos dos canais estudados e os diferentes ligantes, mostrando que é possível se basear em derivados de fármacos conhecidos e toxinas de interesse para ampliar o repertório terapêutico. No entanto, o estudo de ZANATTA et al (2019) demonstra a importância da investigação de fármacos que já são amplamente utilizados, mas que ainda não foram estudados quimicamente com a abordagem de docking molecular.…”