Ligand based Drug Design of New Heterocyclic Imines of GABA Analogues: A Molecular Docking Approach for the Discovery of New GABA-AT Inhibitors

Author(s): Bijo Mathew, Githa E. Mathew, Jerad Suresh, Dhasthakeer Usman, Puthucode N.S. Subramanyan, Kallivalappil F. Safna.

Journal Name: Central Nervous System Agents in Medicinal Chemistry

Volume 17 , Issue 1 , 2017

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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.

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.

Keywords: AutoDock 4.2, docking, GABA, GABA-AT, imine.

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Article Details

VOLUME: 17
ISSUE: 1
Year: 2017
Page: [58 - 63]
Pages: 6
DOI: 10.2174/1871524916666160104143108
Price: $58

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