Yogesh Singh, Jainendra Jain , Partha Chowdhury, Lalit Nainwal
ABSTRACT
Gamma amino butyric acid (GABA) is a major inhibitory neurotransmitter mainly responsible for action of almost all antiepileptic compounds, Gamma amino butyrate amine transferase (GABA-AT) is one of the most important targets in the design and discovery of successful anti-epileptics. Lysine 329A and Arginine 192A are the most widely used residues of GABA-AT for docking studies. In the present paper, twenty one different aryl substituted thiosemicarbazones (PS1-PS21) were studied for interaction with Lys-329A & Arg-192A residues of GABA-AT. Docking studies were carried out using Pyridoxal phosphate (PLP) based method by ‘Vlife Molecular Design Suite 3.5’ software. Grip at docking method, in which both 1OHV and ligand are flexible, was adopted and the results were compared with standard anticonvulsant drug vigabatrin.
In addition, all twenty one molecules were subjected to three dimensional quantitative structure activity relationship (3D QSAR) using Principal Component Regression method (PCR) to design potent anticonvulsant prior to their synthesis. The model gave r2 & q2 values of 0.9587 and 0.9327 respectively for forteen compounds in training and seven compounds of test compounds with optimum number of components as 2.
The model was found to be highly predictive and was further applied to set of ten molecules of aryl substituted thiosemicarbazones. Results of docking studies and 3D QSAR studies have shown that halogen substitution in phenyl ring at Meta position plays important role in protection from seizures. Bromo substituent was found to be more effective as compared to chloro and fluoro substituents.
Thus, it would be worthwhile to synthesize bromo substituted aryl thiosemicarbazones and evaluate their anticonvulsant activity.
Keywords: Anticonvulsant, Docking, 3D QSAR, r2, q2, cross validation, GABA