ORIGINAL RESEARCH QSAR and docking-based computational chemistry approach to novel GABA-AT inhibitors: kNN-MFA-based 3DQSAR model for phenyl-substituted analogs of b-phenylethylidene hydrazine S. K. Bansal • B. N. Sinha • R. L. Khosa Received: 23 October 2009 / Accepted: 17 March 2010 / Published online: 31 March 2010 Ó Springer Science+Business Media, LLC 2011 Abstract c-Amino butyric acid (GABA) is recognized as the principal inhibitory neurotransmitter in the mammalian central nervous system. Attenuation of GABA’ergic neu- rotransmission has been postulated as being involved in the pathophysiology of several CNS disorders. We report here k-nearest neighbor molecular field analysis (kNN-MFA)- based 3DQSAR model for phenyl-substituted analogs of b-phenylethylidene hydrazine as potent inhibitors of GABA transaminase. Overall model classification accuracy was 81.19% (q 2 = 0.8119, representing internal validation) in training set and 67.32% (Pred_r 2 = 0.6732, representing external validation) in test set using sphere exclusion and forward–backward as a method of data selection and var- iable selection, respectively. Keywords c-Amino butyric acid transaminase inhibitors  3DQSAR  k-Nearest neighbor molecular field analysis  b-Phenylethylidene hydrazine Introduction c-Aminobutyric acid (GABA) is recognized as the princi- pal inhibitory neurotransmitters in the mammalian nervous system. It has been estimated that approximately 40% of synapses in the central nervous system are GABA’ergic. Attenuation of GABA’ergic neurotransmission has been postulated as being involved in the pathophysiology of several CNS disorders in humans, for example anxiety, pain, and epilepsy (Andersen et al., 1993). c-Aminobutyrate aminotransferase (GABA-AT) is the enzyme responsible for the degradation of c-aminobutyric acid to succinic semialdehyde. Inhibition of this enzyme results in an increased concentration of GABA in the brain and could have therapeutic applications in neurological disorder including epilepsy, Parkinson’s disease, Hunting- ton’s chorea, and Alzheimer’s disease (Wang and Silverman, 2006). Phenelzine (PLZ; Fig. 1) is a monoamine oxidase (MAO) inhibiting antidepressant which is also effective for treating panic disorder and social anxiety disorders. PLZ is also an inhibitor of GABA-AT and causes a marked ele- vation of brain levels of GABA in rats and gerbils. b-Phenylethylidene hydrazine (PEH; Fig. 2) metabolite of PLZ was found to possess the GABA’eric action of PLZ but had minimal effect on MAO, suggesting that it could be an effective neuroprotective drug without the adverse effects of PLZ. A series of phenyl-ring-substituted PEH derivatives was synthesized and screened to study their effects on GABA metabolism (Sowa et al., 2005). Computational chemistry, prediction of biological activity-based quantitative structure activity relationship (QSAR) substantially increases the potential of work, avoiding time, and resource consuming experiments (Dlaz and Prado, 2008). Many different approaches to QSAR have been devel- oped over the years. The rapid increase in the three- dimensional structural information (3D) of bioorganic S. K. Bansal  R. L. Khosa Department of Pharmacy, Bharat Institute of Technology, Meerut 250103, U.P., India S. K. Bansal (&) House No. L-927, Shastri Nagar, Meerut 250003, U.P., India e-mail: skbansal2003@gmail.com B. N. Sinha Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India e-mail: bnsinha_bit@yahoo.com 123 Med Chem Res (2011) 20:549–553 DOI 10.1007/s00044-010-9350-1 MEDICINAL CHEMISTR Y RESEARCH