Structural analysis of α-glucosidase inhibitors by validated QSAR models using topological and hydrophobicity based descriptors

In the present investigation, QSAR analysis was performed on a data set consist of structurally diverse compounds in order to investigate the role of its structural features on their alpha-glucosidase inhibitory activity. The computational and statistical analyses were performed with V-life MDS and Statistica software. The models derived from multiple linear regression analysis were validated by LOO. LMO, Y-randomization and external test validation methods to investigate its reliability and robustness. The MLR models for the complete data set were also developed with the same descriptors to examine the reliability of the contributed descriptors (in the training set models) for the activity prediction. The validated QSAR models show that the molecular connectivity descriptors (ChiV3cluster and ChiV4), electrotopological descriptors (SdOE-Index and SaasCE-Index) and the hydrophobicity descriptor are contributed significantly for the stability of the models. The molecular connectivity descriptors reveal that the molecules with less number of branches on carbon or hetero atoms along with the presence of electronegative atoms are important for the inhibitory activity. The hydrophobicity descriptor, XKMosthydrophilichydrophobic distance (XKMHD) (calculated by Kellog method using XlogP) demonstrates that the XlogP values between the hydrophobic and hydrophilic distance should be low for favorable activity. The electrotopological descriptors such as the number of oxygen atoms connected with one double bond (SdOE-Index) and the number of carbon atom connected with one single bond along with two aromatic bonds (SaasCE-Index) are favorable for the activity. This study concluded that the presence of balanced hydrophobic and hydrophilic (polar and/or electron negative) properties on the vdW surface area is responsible for hydrogen bonding and other electrostatic interaction (aromatic) of inhibitors with the enzyme for favorable alpha-glucosidase inhibitory activity. (C) 2011 Elsevier B.V. All rights reserved.