hERG inhibition
Imagine your heart as a pump whose beat is timed by tiny electrical gates opening and closing. One of those gates is a potassium channel encoded by the hERG gene; it lets potassium leave heart cells to reset them after each beat. Some drug molecules slip into this channel and plug it, like jamming a doorway, so the reset takes too long.
The hERG channel (also called Kv11.1, carrying the IKr current) has an unusually roomy inner cavity lined with aromatic residues, so it binds a surprisingly wide range of basic, lipophilic molecules. Because so many drugs accidentally fit, hERG inhibition is one of the most common and feared safety liabilities in drug discovery. Blocking it delays the heart's electrical recovery, which shows up on an ECG as a longer QT interval.
A prolonged QT can trigger a dangerous arrhythmia called torsades de pointes, which can be fatal. Medicinal chemists routinely screen compounds against hERG early and redesign molecules to reduce binding, for example by lowering basicity or lipophilicity. Importantly, hERG potency alone is not the whole story: what matters is the margin between the hERG-blocking concentration and the concentration needed for therapeutic effect.
The antihistamine terfenadine was withdrawn because it blocked hERG; its non-cardiotoxic active metabolite, fexofenadine, became the safer replacement.
A classic case where a hERG liability forced a switch to a metabolite-based drug.
A common medicinal-chemistry rule of thumb is to keep the hERG IC50 at least 30-fold above the expected free plasma concentration, though the exact margin depends on the indication and exposure.