title: Ligand based drug design of new heterocyclic imines of GABA analogues: A molecular docking approach for the discovery of new GABA-AT inhibitors.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad -678004, Kerala, India. bijovilaventgu@gmail.com.
authors.forename: Bijo
authors.initials: B
authors.lastname: Mathew
authors.forename: Githa Elizabeth
authors.initials: GE
authors.lastname: Mathew
authors.forename: Jerad
authors.initials: J
authors.lastname: Suresh
authors.forename: Dhasthakeer
authors.initials: D
authors.lastname: Usman
authors.forename: Puthucode Natarajan
authors.initials: PN
authors.lastname: Shiva Subramanyan
authors.forename: Kallivalappil Fathima
authors.initials: KF
authors.lastname: Safna