BPS2026 – Modeling simultaneous binding of drugs and sex-steroid hormones to the hERG channel to predict sex-specific arrhythmia risk

Voltage-gated ion channel proteins are essential in heart rhythm generation. The hERG potassium channel, KV11.1, is responsible for cardiac repolarization, and its blockade by a diverse set of small molecules may lead to prolonged ECG QT intervals and arrhythmias. Additionally, the female sex is known to be an independent risk factor for drug-induced cardiac arrhythmia, and several studies have shown sex hormone interactions with the hERG channel to be a possible direct cause of this risk. We performed AutoDock4 molecular docking with sixty-nine drugs classified by CredibleMeds as QT-prolonging to the hERG channel simultaneously with nine sex-steroid hormones such as estradiol (E2), estrone (E1), ethinylestradiol (EE2), progesterone, dihydrotestosterone (DHT), testosterone, and others. For example, we demonstrated that hERG binding of a potent blocker E-4031 is significantly enhanced by the presence of E2, and to a smaller degree by DHT. The binding cooperativity of drugs and female sex hormones in the channel pore is dependent upon their interactions with aromatic hERG channel residues, namely F656 and Y652 on the pore-lining S6 helix. These findings are in agreement with previous experimental electrophysiology recordings in cultured cells. An analysis of these results shows a consistent pattern of drug-channel interactions which could be crucial to the mechanism of the sex-dependent drug-induced arrhythmia risk. We then used all-atom molecular dynamics simulations followed by end-point binding free energy calculations with MM/PBSA and quantum mechanical interaction energy calculations to provide potentially more accurate energy estimates and confirm our molecular docking findings. We then used our best estimates of drug and hormone binding energies to accurately predict sex-dependent arrhythmia risks for multiple hERG blocking drugs.