Page 34 - FCW, July 2020

COVID-19
tested experimentally to see if they do indeed bind to their targets and, in the case of COVID-19, stop the virus from infecting human cells. The compounds are first tested in cells, then animals and finally humans.
World’s most powerful computer
Since the 1990s, the power of supercomputers has increased by a factor of 1 million or so. Summit at Oak Ridge National Laboratory is currently the world’s most powerful supercomputer, and it has the combined power of roughly 1 million laptops. A laptop today has roughly the same power that a supercomputer had 20 to 30 years ago.
However, in order to gin up speed, supercomputer architectures have become more complicated. They used to consist of single, very powerful chips on which programs would simply run faster. Now they consist of thousands of processors performing massively parallel processing in which many calculations, such as testing the potential of drugs to dock with a pathogen or cell’s proteins, are performed at the same time. Persuading those processors to work together harmoniously is a pain in the neck but means we can quickly try out a lot of chemicals virtually.
Further, researchers use supercomputers to figure out by simulation the different shapes formed by the target binding sites and then virtually dock compounds to each shape. In my lab, that procedure has produced experimentally validated hits — chemicals that work — for each of 16 protein targets that physician-scientists and biochemists have discovered over the past few years. These targets were selected because finding compounds that dock with them could result in drugs for treating a variety of diseases, including chronic kidney disease, prostate cancer, osteoporosis, diabetes, thrombosis and bacterial infections.
Billions of possibilities
34 July 2020 FCW.COM
The Energy Department’s Oak Ridge National Laboratory
is home to Summit, the world’s most powerful supercomputer and an essential tool in the fight against COVID-19.
So which chemicals are being tested for COVID-19? A first approach is trying out drugs that already exist for other indications and that we have a pretty good idea are reasonably safe. That’s called repurposing, and if it works, regulatory approval will be quick.
But repurposing isn’t necessarily being done in the most rational way. One idea researchers are considering is that drugs that work against protein targets of some other virus — such as the flu, hepatitis or Ebola — will automatically work against COVID-19, even when the SARS-CoV-2 protein targets don’t have the same shape.
The best approach is to see if repurposed compounds will actually bind to their intended target. To that end, my lab published a preliminary report of a supercomputer- driven docking study of a repurposing compound database in mid-February. The study ranked 8,000 compounds in order of how well they bind to the viral spike protein. This paper triggered the establishment of a high-performance computing consortium against our viral enemy, announced by President Donald Trump in March. Several of our top- ranked compounds are now in clinical trials.
Our work has now expanded to about 10 targets on SARS-CoV-2, and we’re also looking at human protein targets for disrupting the virus’ attack on human cells. Top- ranked compounds from our calculations are being tested experimentally for activity against the live virus. Several of these have already been found to be active.
Also, we and others are venturing into the wild world of new drug discovery for COVID-19 – looking for compounds that have never been tried as drugs before. Databases of billions of these compounds exist, all of which could probably be synthesized in principle but most of which have never