A comparative 2D QSAR study on a series of hydroxamic acid-based histone deacetylase inhibitors vis-à-vis comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

ABSTRACT

A quantitative structure-activity relationship (QSAR) study was performed on a series of indole amide analogues reported by Dai et al. [Bioorg Med Chem Lett (2003), 13, 1897-1901] to act as histone deacetylase (HDAC) inhibitors. The multiple regression analysis (MRA) revealed a model showing the significant dependence of the activity on molar refractivity (MR) and global topological charge index (GTCI) of the compounds, suggesting that inhibition of the HDAC by this series of compounds might involve the dispersion interaction with the receptor, where charge transfer between pairs of atoms might greatly help to polarize the molecule. The MRA results were then compared with those obtained by Guo et al. [Bioorg Med Chem (2005), 13, 5424-5434] by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). It was found that MRA gave as good results and had as good predictive ability as CoMFA and CoMSIA. Besides, MRA was also able to throw the light on the physicochemical properties of the molecules that were involved in drug-receptor interactions, while CoMFA and CoMSIA could not. The dispersion interaction between the molecule and the active site of the receptor is suggested to be the main interaction.