Chapter 34 - hERG Methods

Abstract

Regulatory agencies insist on having experimental hERG data for all compounds moving into clinical development because of the risk of death from arrhythmia in a small portion of the population. Pharmaceutical companies need to develop a strategy for hERG block assessment during drug discovery to avoid investment in a chemical series that has significant risk. There is an emerging trend to begin screening for potential hERG blocking by applying in silico tools to hits from high-throughput screening. It is useful for drug research companies to have tools for in silico, in vitro, and in vivo hERG testing to meet the needs at each stage of discovery. Various methods for hERG are summarized. Structural features associated with hERG blocking are discussed. In vitro hERG methods can be classified into two types. Indirect methods (membrane potential-sensitive dye, ligand binding, rubidium efflux) measure effects associated with K+ ion channel activity. The other type of method, high-throughput patch clamp, directly measures ion channel activity and has emerged as the in vitro method of choice. The implementation of hERG screening in drug discovery is also reviewed.