HERG QSAR model

Dearden JC, Netzeva TI. QSAR modelling of hERG potassium channel inhibition with low-dimensional descriptors. I Pharm Pharmacol 2004 56 Suppl S-82. 

Indeed, considering the latter 3D QSAR model, the features that make a molecule suitable to bind to the hERG channel start delineating in a chemically interpretable manner, but, it is rather dear how these kinds of models emphasize mostly the 3D steric aspects of molecules, depending mainly on factors such as the conformation (or the conformational analysis protocol) or the alignment of the molecules. To obtain a description of the characteristics of hERG-blocking molecules in terms of measurable (computable) properties in a way that the physicochemical determinants of the activity can be identified, the classical 2D QSAR approach is well suited. 

In an independent study, Yoshida and Niwa [20] analyzed a larger and more diverse set of molecules (104 compounds) and developed a 2D QSAR model, which gave results similar to that of Cronin [19] but added some more details with regard to the physicochemical properties involved in the hERG blockade by drugs. Equation 5.2 represents the best model ... 

The relevance of size-related properties of hERG-blocking molecules was also detected in a 2D QSAR model developed by Coi et al. [22] after the analysis of 82 compounds through the CODESSA method. These authors developed two multiparameter models with strong predictive properties, from which, besides the involvement of hydrophobic features, the importance of linearity as opposed to globularity of the hERG blockers emerged. 

In Table 5.1, we present a list of the main physicochemical and structural properties associated with the descriptors included in the 2D QSAR models discussed above. Of course, we did some generalizations in an attempt to refer different parameters and descriptors to the same property, but the effort was devoted at identifying the smallest number of significant features positively or negatively correlated to the hERG blockade by small molecules. Examining the properties... 

Table 5.1 Molecular properties identified as relevant in 2D QSAR models of hERG blockade by small molecules.

Gomplex field-based 3-D QSAR models have also been applied to the problem of predicting hERG activity. Gavalli ef al. [85] used a CoMFA model, as previously discussed. Pearlstein ef al. [89] modeled a set of sertindole analogs using compara-... 

While most reports in the literature employ a modified version of Lipinski s Rule-of-Five criteria, a few have used models that are more sophisticated as part of the design. Many QSAR models have been reported in the literature for many different ADMET related properties, from solubility to permeability to hERG inhibition to metabolic stability. Several recent... 

Keseru [35] used literature data on 55 compounds to train a QSAR model based on a number of calculated descriptors. Five descriptors were used clogP, calculated molar refractivity (CMR), partial negative surface area, and the VolSurf W2 (polarizability) and D3 (hydrophobicity) descriptors. A model of acceptable quality was obtained (f = 0.94, SSE = 0.82) and tested on a 13 compound holdout set (r2 = 0.56, SSE = 0.98). An HQSAR model was then created that made use of 2D fragment fingerprints (threshold hERG IC50 = lpM). The best HQSAR model was validated on a holdout set of 13 compounds (f = 0.81, SSE = 0.67). 

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