“Using the VirtualFlow software which we developed a good year ago now, we have succeeded in conducting in the shortest time the world’s largest virtual screening program of substances with a potential impact on SARS-CoV-2,” reports Dr. Christoph Gorgulla, postdoc at Harvard Medical School and alumnus of the Berlin Mathematical School (BMS). The results of this screening have now been published in the iScience open access journal.
Among the researchers involved in developing the VirtualFlow software was Dr. Konstantin Fackeldey, associate professor at TU Berlin and co-author of the publication. “VirtualFlow enables us to simulate the binding strength and binding affinity of specific substances with each other. In this screening, we examined the binding affinity of over one billion potential substances at 35 different binding sites of 15 SARS-CoV-2 virus proteins. These substances, also known as ligands, are mainly taken from the database of a company that produces commercial chemical molecules for the pharmaceutical industry. However, the databases of dozens of other companies were also screened.
In addition, the binding affinity of these ligands was also analyzed at a number of binding sites of two human proteins. We know that these proteins interact with the virus on a cellular basis to allow infection to occur,” Fackeldey explains.
A total of almost 50 billion docking procedures have been simulated. A docking procedure can be likened to adding a piece to a 3D puzzle. In principle, some 50 billion attempts have been made to connect one piece of the 3D puzzle (the ligand) with another (the virus protein) as tightly as possible and to determine the binding strength.
“The 15 virus proteins include proteins which are responsible for the binding of SARS-CoV-2 cells onto human cells as well as proteins responsible for replicating the virus RNA or creating the viral shell. The goal is to ‘switch off’ these proteins by introducing a particular ligand, as the two substances bind tightly. This would stop the virus replicating or at least inhibit the process. Elsewhere, binding ligands to human proteins could prevent viruses from entering cells,” says Gorgulla, explaining the objective of the research.
During the course of the screening, the international team of researchers has identified several thousand substances displaying a promising binding affinity to virus proteins or human proteins. “We have made all our findings freely available. It is not possible for any individual team working alone to validate all possible agents. We also have to bear in mind that traditional methods for discovering agents are very expensive and require a lot of time. However, we need to proceed very quickly to combat the pandemic. This is why we very much hope that our findings will benefit other research teams all over the world with their experiments into potential agents,” says Gorgulla.
The main advantage of the research is that the screened substances also include substances which have already been approved as drugs for other illnesses as well as completely new and little researched substances. If the former prove effective as virus inhibitors, this will dramatically simplify the normally lengthy process of obtaining approval. Other bindings which emerged as top hits in the VirtualFlow screening are already being examined in clinical studies for COVID-19, including a number of steroid drugs. In such cases, researchers can build on the findings of the screening process and more precisely analyze how these medications function at the molecular level - something which is not always researched, even when lab data show that an agent works well.
“Examining dozens of binding sites for 17 proteins in parallel could also help simultaneously identify or develop several drugs which could be used in tandem to combat the virus on several different fronts. This would open up new opportunities for medicine to stop the virus and respond to new mutations,” Fackeldey concludes.