Dozens of commonly used drugs, including antibiotics, anti-nausea drugs, and cancer, have the potential side effect of prolonging the electrical event that causes contraction, causing an irregular heartbeat, or an abnormal heart rhythm called acquired long QT syndrome. Some of these drugs, while safe at their current dosages, may have more therapeutic benefits at higher doses, but are limited by the risk of arrhythmia.
Through both computational and experimental validation, a multi-institutional team of researchers has identified a compound that prevents the prolongation of the electrical event or action potential of the heart, an important step towards safer use and expanded therapeutic efficacy of these drugs when ingested leads combination. The team found that the compound called C28 not only prevents or reverses the negative physiological effects on action potential, but also does not cause a change in normal action potential when used alone at the same concentrations. The results, found through rational drug design, were published online on the Internet on Friday, May 14th Procedure of the National Academy of Sciences.
The research team was led by Jianmin Cui, professor of biomedical engineering at 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 of Molecular Cardiology at Stony Brook University’s Renaissance School of Medicine; and Xiaoqin Zou, professor of physics, biochemistry and a member of the Dalton Cardiovascular Research Center and the Institute of Data Science and Computer Science at the University of Missouri.
The drugs in question, as well as some that have been withdrawn from the market, cause a prolongation of the heartbeat’s QT interval, known as acquired long QT syndrome, which predisposes patients to arrhythmias and sudden death. In rare cases, Long QT can also be caused by specific mutations in genes that code for ion channel proteins that conduct the ion currents to create the action potential. Although there are several types of ion channels in the heart, a change in one or more of them can lead to this arrhythmia, which results in approximately 200,000 to 300,000 sudden deaths per year, more than deaths from stroke, lung cancer, or breast cancer.
The team selected a specific target, IKs, for this work because it is one of the two potassium channels that are activated during the action potential: IKr (fast) and IKs (slow).
“The fast plays an important role in the action potential,” said Cohen, one of the world’s leading electrophysiologists. “If you block it, you get a long QT and you get a long action potential. IKs are very slow and contribute much less to the normal duration of the action potential. “
It was this difference in roles that suggested that increasing IKs might not significantly affect normal electrical activity, but could shorten a prolonged action potential.
Cui, an internationally recognized expert on ion channels, and the team wanted to find out whether the lengthening of the QT interval could be prevented by compensating for the change in current and inducing the long QT syndrome by improving the IKs. They identified a location in the voltage-sensing domain of the IK potassium ion channel that small molecules could access.
Zou, an internationally recognized expert who specializes in developing new and efficient algorithms to predict protein interactions, and the team used the atomic structure of the KCNQ1 unit of the IKs channel protein to create a library of a quarter of a million small compounds targeted at was to computationally screen this voltage sensing domain of the KCNQ1 protein entity. To do this, they developed software called MDock to test the interaction of small compounds with a particular protein in silico or mathematically. By identifying the geometric and chemical features of the small compounds, they can find the one that fits into the protein – a kind of high-tech 3D puzzle. While it sounds simple, the process is quite complicated as it involves charge interactions, hydrogen bonds, and other physicochemical interactions of both the protein and the small compound.
“We know the issues and the path to great progress is to identify and address the weaknesses and challenges,” said Zou. “We know the functional and structural details of the protein so that we can use an algorithm to dock each molecule to the protein at the atomic level.”
One after the other, Zou and her laboratory coupled the potential compounds to the protein KCNQ1 and compared the binding energy of each one. They selected about 50 candidates with very negative or tight attachment energies.
Cui and his lab then identified C28 using experiments from the 50 candidates identified in silico by Zou’s lab. They validated the docking results by measuring the shift in voltage-dependent activation of the IKs channel at different concentrations of C28 to confirm that C28 actually improves IKs channel function. They also examined a number of genetically engineered IKs channels to reveal the binding of C28 to the site for in silico screening.
Cohen and his laboratory tested the C28 compound in ventricular myocytes using a small mammalian model that expresses the same IK channel as humans. They found that C28 can prevent or reverse the drug-induced prolongation of electrical signals across the heart cell membrane and have a minimal effect on normal action potentials at the same dose. They also found that there was no significant effect on the atrial muscle cells, an important control for the potential use of the drug.
“We’re very excited about it,” said Cohen. “In many of these drugs, a concentration of the drug is acceptable, and at higher doses it becomes dangerous. If C28 can eliminate the risk of QT prolongation, these drugs can be used in higher concentrations and, in many cases, become more therapeutic. “
While the compound needs additional verification and testing, the researchers say there is tremendous potential for this or similar compounds and could help transform second-line drugs into first-line drugs and bring others back to market. With the help of the Washington University Office of Technology Management, they patented the compound, and Cui created a startup company, VivoCor, to continue working on the compound and others they like as potential drug candidates. The work was accelerated in 2018 by a LEAP (Leadership and Entrepreneurial Acceleration Program) grant from Washington University in St. Louis, funded by the Office of Technology Management, the Institute for Clinical and Translational Sciences, the Center for Drug Discovery, and the Center for Drug Discovery funded research innovation in biotechnology and the Skandalaris center for interdisciplinary innovation and entrepreneurship.
“This work was carried out with an effective approach to drug design: identifying a critical point in the ion channel based on an understanding of the structure-function relationship, using in-silico docking to identify compounds that interact with the critical point in the ion channel , Validating the functional modulation of the ion channel by the compound and showing therapeutic potential in heart muscle cells, ”said Zou. “Our three laboratories make a great team, and without one of them it would not be possible.”