Abstract:
Temporal Lobe Epilepsy (TLE) is the most prevalent chronic disorder of the nervous
system. It is a recurring form of drug-resistant focal (partial) epilepsy that affects the two
temporal lobes of the brain. Brain's injuries, infections, inflammations, tumors,
developmental abnormalities, genetic mutations, strokes, heart attacks, and neuronal cell
death are reported to cause scraping in the temporal lobe that leads to Mesial Temporal
Lobe Epilepsy or Hippocampal Sclerosis (HS). The neuronal damage initiates functional
modifications in substantial membrane depolarization and failure in synaptic transmission
and hyperexcitability. Hyper-excited neurons instigate focal seizures in the temporal lobe
due to the activation of glutamate receptors. Failure of synaptic transmission due to
hyperexcitation triggers a signal for the induction of neuronal cell death pathway and the
activation of Death Associated Protein Kinase-1 (DAPK-1). It is a pro-apoptotic Ser/Thr
kinase protein that controls neuronal death signaling processes, such as apoptosis and
autophagy. In ER stress signaling, DAPK-1 acts as a critical integration point because it
forms direct interaction with NMDA receptor subunits. This interaction increases
conductance for glutamate and induces brain damage by an ischemic stroke, ultimately
causing focal seizures. In the present research study, DAPK-1 was identified as a
potential target for the treatment of TLE. In molecular docking, all the specific inhibitors
of DAPK-1 were docked at the binding site. Molecular dynamic simulation highlighted
the role of the different regions (Entrance, Hinge, glycine-rich, and substrate-binding
motif) that were crucial for selectivity and specificity. The binding residues of the target,
such as Leu19, Glu94, Val96, and Glu100 were involved in stable interactions with
highly actives ligands. The most stable complex, after MD, was selected for the
pharmacophore model. This model contains one hydrophobic, one donor, and two
acceptor hydrogen bond features. The developed model displayed 100% accuracy,
sensitivity, specificity, and precision values. The model was used to screen the Zinc
database containing natural compounds. Interestingly, some of the identified hits were
used in the treatment of epilepsy by reducing the severity of seizures which further
strengthen the applicability of our proposed pharmacophore model.
