hERG binding feature analysis of structurally diverse compounds by QSAR and fragmental analysis

Abstract

A series composed of structurally diverse hERG blockers was considered for the present hERG binding feature analysis. The QSAR models derived from the analysis were validated which revealed that the developed models (biparametric) are statistically significant. In all the models, the SlogP_VSA9 descriptor has contributed along with either MOPAC (AM1_HOMO or AM1_IP) or partial charge (PEOE_VSA-6) descriptors. These descriptors describe that the molecules should have functional groups with less negative charge and/or high ionization potential for better activity. Fragmental analysis was also performed on the substituents present in the molecules, and reveals that the presence of a COOH group is detrimental for the activity and also it reduces the partition coefficient of the molecule. The presence of an aromatic substituent significantly improves the activity and, simultaneously, increases the partition coefficient value of the molecule. These findings suggest that the partition coefficient is one of the important properties for the hERG blocking activity of the studied molecules. The additive effect of the partition coefficient (SlogP_VSA9) and the negative charge on the van der Waals surface area of the molecules was analyzed by using the multiplied values of the descriptors (multiplication of descriptor with their respective regression coefficient). These studies confirm that the presence of a less negatively charged group with aromatic rings is favourable for hERG blocking activity. Hence, the results obtained from the studies are useful for developing novel moieties with reduced hERG blocking activities.