McKelvey School of Engineering

Compound may prevent risk of form of arrhythmia from common medications

(1) Model the KCNQ1 structure and define the binding site; (2) Generate the binding site spheres to represent the curvatures (and thereby the shape) of the binding site. (3) Dock compounds from the Available Chemicals Directory using MDock by matching the atomic centers of each compound with the binding site spheres. (4) Evaluate the chemical interactions between each compound and the protein with the docked geometries and rank the compounds. On the molecular surface of KCNQ1, red (blue) represents negatively (positively) charged region, and gray means uncharged region. C28 is represented in stick mode. (Image: University of Missouri-Columbia)

Through both computational and experimental validation, a multi-institutional team of researchers has identified a compound that prevents the lengthening of the heart’s electrical event, or action potential, resulting in a major step toward safer use and expanded therapeutic efficacy of these medications when taken in combination.

The team found that the compound, named C28, not only prevents or reverses the negative physiological effects on the action potential, but also does not cause any change on the normal action potential when used alone at the same concentrations. The results, found through rational drug design, were published online in Proceedings of the National Academy of Sciences (PNAS) on May 14.


The research team was led by Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis; Ira Cohen, MD, PhD, Distinguished Professor of Physiology and Biophysics, professor of medicine and director of the Institute for Molecular Cardiology at the Renaissance School of Medicine at Stony Brook University; and Xiaoqin Zou, professor of physics, biochemistry and a member of the Dalton Cardiovascular Research Center and Institute for Data Science and Informatics at the University of Missouri.

The drugs in question, as well as several that have been pulled from the market, cause a prolongation of the QT interval of the heartbeat, known as acquired Long QT Syndrome, that predisposes patients to cardiac arrhythmia and sudden death. In rare cases, Long QT also can be caused by specific mutations in genes that code for ion channel proteins, which conduct the ionic currents to generate the action potential.

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