The researchers are taking the next steps in their computational pipeline to expand the set of drugs screened for cardiotoxicity, looking at a variety of agents that have been part of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) safety pharmacology testing group. They’re also working with the biopharmaceutical company Amgen to get blinded compounds for their screening.”The idea is that Amgen would give us the chemical structures of the drugs, but we wouldn’t know whether they were proarrhythmic or not,” Clancy said. “Then we’ll use the pipeline to make some predictions about those drugs, and send those results back where they will reveal if our model was accurate in predicting what they’ve seen.”Clancy and team also want to move the research into a personalized medicine approach, building models of an individual’s cellular electrophysiology that include some genetic background. One project cultures heart muscle cells from individuals to develop a model called the “induced pluripotent stem cell derived cardiac myocyte.””The benefit of a personalized medicine approach is that it includes all of the genetic information in the background, so you can screen drugs and then start to ask, ‘Why are some individuals susceptible to drugs and proarrhythmia from drugs and other people aren’t?’ We may even be able to work towards developing reconstructions of their hearts in silico,” Clancy said.A longtime collaborator of Clancy’s at Johns Hopkins, Natalia Trayanova, has developed high resolution three-dimensional models based on CT or MRI imaging of individual hearts. The hope is to use a finite element approach to populate the three-dimensional reconstructions with their own electrophysiology. “That’s what we’re thinking about in the next five to 10 years,” Clancy said.In the shorter term, Vorobyov was awarded allocations in April 2020 on the NSF-funded Frontera supercomputer at TACC to scale up his calculations. “We want to test this on many more different types of drugs, including the prospective COVID-19 therapeutics. This allocation will help run many of these drugs in parallel. Frontera, on which we recently got 200,000 node hours to use as part of our LRAC award, is one of the world’s most powerful supercomputers and offers unprecedented possibilities for improving efficiency and scalability of our simulations. We will be able to run simulations for several hERG blocking drugs in parallel in a matter of few weeks, which will greatly accelerate development of our multi-scale safety pharmacology pipeline.”The study, “A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm” was published February 24, 2020, in the journal Circulation Research. The study co-authors are Pei-Chi Yang, Kevin R. DeMarco, Parya Aghasafari, Mao-Tsuen Jeng, John R.D. Dawson, Vladimir Yarov-Yarovoy, Igor Vorobyov, Colleen E. Clancy of the University of California, Davis; Slava Bekker of American River College; Sergei Y. Noskov of University of Calgary, Alberta, Canada. The study was funded by the National Institutes of Health, the American Heart Association and other agencies.

Source: Jorge Salazar at TACC

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