Mohd Salman, Sisir Nandi
Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur, Uttarakhand, India
Abstract: Quantitative structure–activity relationship (QSAR) and pharmacophore models have been developed in the present study to predict mode of binding of highly active aminopyridazine derivatives of γ-aminobutyric acid (GABA) acting as selective GABA-A receptor antagonists against induced coma. Descriptor-based QSAR model has been validated internally and by calculating applicability domain. Pharmacophore model predicted the important structural features including hydrophobicity and aromaticity at sixth position and aliphatic hydrophobic substituents must be substituted at fourth position of the aminopyridazine nucleus. Thus, the net aromaticity of the ligand may be enhanced by creating electron-rich environment nearer to the 3-amino cationic center of the aminopyridazine ring that are very much crucial for the inhibition of [3H] GABA-A receptor binding. The aromatic ligand may interact with the aromatic amino acid residues of pentameric structure of target. Finally, structure-based molecular docking study was performed for better interpretation of the mode of binding of the aminopyridazine compounds toward GABA-A target. Theoretical modeling utilizing molecular descriptor-based QSAR, pharmacophore generation, and molecular docking analysis of selective GABA-A receptor antagonists has not yet been reported. Therefore, this study has significant impact for designing of the highly active compounds in this series that are useful for the treatment of coma induced by drugs or chemicals.
Keywords: GABA-A receptor antagonists, QSAR, pharmacophore, molecular docking, induced coma
Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur, Uttarakhand, India
Abstract: Quantitative structure–activity relationship (QSAR) and pharmacophore models have been developed in the present study to predict mode of binding of highly active aminopyridazine derivatives of γ-aminobutyric acid (GABA) acting as selective GABA-A receptor antagonists against induced coma. Descriptor-based QSAR model has been validated internally and by calculating applicability domain. Pharmacophore model predicted the important structural features including hydrophobicity and aromaticity at sixth position and aliphatic hydrophobic substituents must be substituted at fourth position of the aminopyridazine nucleus. Thus, the net aromaticity of the ligand may be enhanced by creating electron-rich environment nearer to the 3-amino cationic center of the aminopyridazine ring that are very much crucial for the inhibition of [3H] GABA-A receptor binding. The aromatic ligand may interact with the aromatic amino acid residues of pentameric structure of target. Finally, structure-based molecular docking study was performed for better interpretation of the mode of binding of the aminopyridazine compounds toward GABA-A target. Theoretical modeling utilizing molecular descriptor-based QSAR, pharmacophore generation, and molecular docking analysis of selective GABA-A receptor antagonists has not yet been reported. Therefore, this study has significant impact for designing of the highly active compounds in this series that are useful for the treatment of coma induced by drugs or chemicals.
Keywords: GABA-A receptor antagonists, QSAR, pharmacophore, molecular docking, induced coma
