3-D-QSAR of N-substituted 4-amino-3,3-dialkyl-2(3H)-furanone GABA receptor modulators using molecular field analysis and receptor surface modelling study.
We report the theoretical validation of the experimentally observed structure-activity relationships (SAR) of a set of N-substituted 4-amino-3,3-dialkyl-2(3H)-furanone GABA receptor modulators showing positive allosteric modulatory activity of the GABA(A) receptor similar to that shown by Loreclazole. Efforts were made to explain some of the conclusions drawn during this study based on a solitary instance of occurrence of the observation within the dataset. Some of the conclusions selected for study included (i) the enhanced activity for the R enantiomer of a compound, (ii) enhanced activity for a compound with an amide type functionality vis-à-vis an amine type functionality at C-4, (iii) enhanced activity for a compound with a carboxamide or carbamate type functionality linking the end group at C-4 over a compound with only the end group attached, provided the alkyl groups attached at C-3 are identical in both cases. The 3-D-QSAR method of molecular field analysis along with receptor-ligand complex stability studies were found to be the most suitable for explaining these activities. While the first conclusion was comprehensively proven, significant support was obtained in case of the latter two. Further comprehensive study is underway and we hope to report them shortly.
Ghoshal
Nanda
N
Drug Design, Development and Molecular Modelling Division, Indian Institute of Chemical Biology (CSIR), Kolkata, India. nghoshal@iicb.res.in
Mukherjee
Prasenjit K
PK
D005663:Furans / Q000737:chemistry*; D018757:GABA Modulators / Q000737:chemistry*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D018079:Receptors, GABA / Q000378:metabolism*; D013499:Surface Properties
D005663:Furans; D018757:GABA Modulators; D018079:Receptors, GABA