Background: Degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is
mainly catalysed by GABA aminotransferase (GABA-AT), excessive activity of which leads to convulsions.
Inhibition of GABA-AT increases the concentration of GABA and can terminate the convulsions.
Several studies have revealed that GABA analogues could be the outstanding scaffolds for the design of
potent inhibitors of GABA-AT. The poor ability of GABA analogues to cross the blood–brain barrier
(BBB), always produces low therapeutic index.` However, Vigabatrin, a mechanism-based inhibitor of
GABA-AT, is currently approved treatment of epilepsy, but it has harmful side effects, leaving a need
for improved GABA-AT inactivators.
Experimental design: In our present in silico investigation, AutoDock 4.2,-based on Lamarckian genetic
algorithm was employed for virtual screen of a compound library with 35 entries (Schiff’s bases of
GABA) in search for novel and selective inhibitors of GABA-AT.
Results: By means of flexible type of molecular docking, we proposed that these designed molecules
could successfully bind into the active pocket of GABA-AT with good predicted affinities in comparison
to standard vigabatrin. Among the designed analogues, HIG18, HIG28 and HIG30 showed significant
binding free energy of -10.25, -9.88 and -9.31 kcal/mol with predicted inhibitory constant values of
0.03, 0.05 and 0.15 μM respectively.
Conclusion: Using ligand-based drug design, we proposed that electron withdrawing phenyl substituted
heterocyclic imines of GABA could be considered as promising structures for synthesis and testing of
new GABA-AT inhibitors from this class. We hypothesize that novel GABA analogues with an azomethine
linkage incorporated with heterocyclic system can have increased affinity and more lipophilic
character that would provide a probability of having less toxic effect in the therapy of convulsions.