HERG binding

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Song, M. and Clark, M. (2006) Development and evaluation of an in silico model for hERG binding. Journal of Chemical Information and Modeling, 46, 392—400. 

This structure-based strategy was found to be very successful. All compounds in this series maintained excellent 5-HT1A affinity and a broad 5-HT /aj selectivity window while significantly reducing hERG binding by factors ranging from fivefold to more than 10-fold. 

Fig. 15.19 Exampies of the distribution of predicted hERG binding iikeiihood for diversity reagents within a 2400-member iibrary buiit around a common core. Binding to the hERG channei was predicted according to the method reported by Roche scientists [77]. Predicted scores of iess than 0.3 are flagged as potential for concern. Scores above 0.7 are not flagged as potential hERG binders. There is no basis for interpretation for scores between 0.7 and 0.3.

The key to these assays is to find a suitable method by which the bound labeled ligand can be measured, separate from the unbound fraction. Three separate methods have been used to measure hERG binding filtration through glass fiber filters [36, 37], scintillation proximity assay (SPA) technology [38] and fluorescence... 

Bains W, Basman A, White C. HERG binding specificity and binding site structure Evidence from a fragment-based evolutionary computing SAR study. Prog Biophys Mol Biol 2004 86 205-33. 

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