Abstract
Quantitative structure activity relationship study (QSAR) and molecular docking were used to design and virtually screen some new N-benzylacetamide derivatives for their ability to inhibit ?-amino butyrate-aminotransferase. Ninety compounds with anticonvulsant activity against maximal electroshock induced seizures were used for QSAR study. B3LYP/6-31G** quantum mechanical method was employed to optimize/minimize the molecular structure of these compounds. Genetic Function Algorithm (GFA) method was used to develop the QSAR models. Each model gave an octa-parametric equation with good statistical qualities (R2 ranged from 0.823 to 0.893, Q2 from 0.772 to 0.854, F from 36.53 to 37.10, R2pred(test) from 0.768 to 0.893). Information obtained from the parameter contained in the model suggested that increasing the molecular mass and linearity of molecule would lead to increase in anticonvulsant activity of studied compounds. These informed the design and virtual screening of 118 new N-benzylacetamide derivatives using 2-acetamido-N-benzyl-2-(5-methylfuran-2-yl)acetamides as the template. The designed molecules were docked with ?-amino butyrate-aminotransferase (GABA_AT; PDB: 1OHV) using Internal Coordinate Mechanics Program (ICM-pro 3.8-3). The binding affinity of the designed compounds with GABA_AT were comparable to that of 4-aminohex-5-enoic acid (vigabatrin) and 3, 3-diphenylpyrrolidine-2, 5-dione (phenytoin) and 5H-dibenzo [b,f]azepine-5-carboxamide (carbamazepine), which are known inhibitors of GABA_AT. Therefore, the designed molecules have potential as inhibitors of GABA_AT and consequently as anticonvulsant agent.
Highlights
One of the major inhibitory amino acid neurotransmitter of the mammalian central nervous (CNS) system is γ-amino butyric acid (GABA)
The rule recommended that the ratio of descriptors to compounds used for building a model should not exceed 1:5; otherwise the risk of chance correlation is high
Validated quantitative structure activity relationship study (QSARs) models were developed for the anticonvulsant activity of some N-benzyl actetamide derivatives
Summary
One of the major inhibitory amino acid neurotransmitter of the mammalian central nervous (CNS) system is γ-amino butyric acid (GABA). Reduction of its concentration in the brain has been implicated in symptoms associated with epilepsy and several other neurodegenerative/psychiatric conditions like stroke, anxiety, schizophrenia and so on (WHITING, 2003). The enzyme γ-amino butyrate-aminotransferase (GABA_AT) catalyzes the degradation GABA to succinic semi aldehyde thereby reducing its level in the brain. Inhibition of the activity of GABA_AT is a way to raise cerebral concentrations of GABA and this has become the target for many anticonvulsant drugs. Numerous anticonvulsant molecules (antiepileptic drugs, AEDs) that inhibit the action of GABA_AT have been developed over the years e.g. 4-aminohex-5-enoic acid (vigabatrin) (PAOLA et al, 2004). In this light, developing new molecule with enhanced antiepileptic activity and lessened side effect is a fundamental task for medicinal science
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