New Insights into Ion Channels: Predicting hERG-Drug Interactions

Abstract

Drug-induced long QT syndrome can be a very dangerous side effect of existing and developmental drugs. In this work, a model proposed two decades ago addressing the ion specificity of potassium channels is extended to the human ether-à-gogo gene (hERG). hERG encodes the protein that assembles into the potassium channel responsible for the delayed rectifier current in ventricular cardiac myocytes that is often targeted by drugs associated with QT prolongation. The predictive value of this model can guide a rational drug design decision early in the drug development process and enhance NCE (New Chemical Entity) retention. Small molecule drugs containing a nitrogen that can be protonated to afford a formal +1 charge can interact with hERG to prevent the repolarization of outward rectifier currents. Low-level ab initio calculations are employed to generate electronic features of the drug molecules that are known to interact with hERG. These calculations were employed to generate structure-activity relationships (SAR) that predict whether a small molecule drug containing a protonated nitrogen has the potential to interact with and inhibit the activity of the hERG potassium channels of the heart. The model of the mechanism underlying the ion specificity of potassium channels offers predictive value toward optimizing drug design and, therefore, minimizes the effort and expense invested in compounds with the potential for life-threatening inhibitory activity of the hERG potassium channel.

Keywords: Torsades de Pointes; ab initio calculations; drug development; human ether-à-gogo-related gene (hERG); long QT syndrome; potassium channel; structure–activity relationships (SAR).

Figure 1

(A) Representative depiction of an extracellular view of a voltage-gated potassium channel. Ribbon representation of the hERG channel. The image was generated using Schrӧdinger Maesto and importing the PDB: 5VA1 3.70 Å structure [2], including the biological unit. The ribbons are colored by residue position using the default palette in Schrӧdinger Maestro. (B) Representative sketch of a mass spectrometry quadrupole.

Figure 2

Protonated amines atomic charge, pKa vs. HF/321G NBO data.

Figure 3

(A): Table 1 Compounds HF/321G NBO vs. Mulliken Charge. (B): NBO vs. Mulliken Charge, secondary and tertiary amines; Table 1 protonated compounds after questions 1–5.

Scheme 1

hERG channel prediction flow chart for first compound set.

Scheme 1

hERG channel prediction flow chart for first compound set.

Figure 4

Examples of hERG interaction trend predictions, (A) Astemizole template. Removal of the -CH2- should give rise to a molecule whose protonated nitrogen undergoes a ‘field effect’ and thus should give rise to a molecule that has a higher hERG IC₅₀. (B) Clozapine template. (C) Rupatadine template. (D) Olanzapine template.

Figure 4

Examples of hERG interaction trend predictions, (A) Astemizole template. Removal of the -CH2- should give rise to a molecule whose protonated nitrogen undergoes a ‘field effect’ and thus should give rise to a molecule that has a higher hERG IC₅₀. (B) Clozapine template. (C) Rupatadine template. (D) Olanzapine template.