A computational model using ab initio calculations generated structure-activity relationships to predict the potential of small molecule drugs to inhibit hERG potassium channels.
An extended computational model using ab initio calculations can predict hERG-drug interactions, offering a tool to screen out compounds with QT-prolonging potential early in drug development.
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.
Michael F. Wempe (Wed,) conducted a other in Drug-induced long QT syndrome. Small molecule drugs containing a protonated nitrogen was evaluated on hERG potassium channel inhibition. A computational model using ab initio calculations generated structure-activity relationships to predict the potential of small molecule drugs to inhibit hERG potassium channels.