Epilepsy is a neurological disease with no defined cause, characterized by recurrent epilep-
tic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the
central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients
require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the
discovery of new substances from natural products that can combat epileptic seizures. Using in silico
techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid
derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phe-
nylpropanoid compounds to predict biological activities. The LBVS were developed for the targets al-
pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel T-
type (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1
(GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel
(NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were
analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters,
and later, the best molecules were evaluated in the molecular docking consensus. The TR430 com-
pound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did
not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either
from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with
GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and sig-
nificant interactions with both targets. The studied compound showed to be a promising molecule with
a possible multi-target activity in both fundamental pharmacological targets for the treatment of epi-
lepsy.
