Last year, when Italy was besieged by COVID-19, scientists from Exscalate4Cov, a public-private consortium of 18 institutions across Europe led by the Italian pharmaceutical company Dompé Farmaceutici, had just begun their search for a drug. therapeutic against COVID-19. Eight scientists, all located across Europe, gathered in a virtual room to discuss potential molecules. Each scientist held a three-dimensional representation of a molecule that they simulated and traversed the others through it. Within this space, scientists could search these molecules, separating them, expanding them, and attaching them to possible compounds. Questions were asked and the chances of success and failure of each venue were outlined on a virtual whiteboard. This virtual configuration also allowed them to compare molecules side by side.
Armed with $ 3 million in European Union funding, the group provided suggestions for treatments and analyzed them using supercomputers. In October they had presented their first candidate for a phase III clinical trial in Europe: a generic osteoporosis drug called Raloxifene.
The trial is over. “We are awaiting the final results, but we are very confident of the possible success of the clinical trial,” says Andrea Beccari, chief scientist at Excalate and head of research and development of Dompé Pharmaceutical platforms. The result will not only determine whether Raloxifene will work against COVID-19, but could also inform the design of new drugs.
To create a new drug, scientists first analyze how a disease enters human cells and then design a mechanism to interfere with that infection. Traditionally, they have done this on paper, sketching proteins and simulating how a molecule or compound could bind to it. Current software often does not provide enough visual landscape for scientists to understand the full range of how molecules relate, especially those with multiple binding sides. That’s why Exscalate worked with a company called Nanome, which hopes to accelerate drug development by giving scientists a way to visualize molecules in the three-dimensional space of an Oculus headset.
Beccari said that using supercomputers, the group took a list of 400,000 potential molecules and simulated their ability to adhere to COVID-19 virus proteins. In addition to analyzing them through computers, they also used virtual reality to better understand how these compounds could bind to COVID-19 viral proteins and how they would work in humans. What was important to predict was whether a drug would be able to reach the lungs.
“For example, Remdesivir, which is a very good antiviral molecule, has very little effect on humans just because it doesn’t reach the lungs in a sufficient concentration,” says Beccari. But in their analysis supported by machine learning, they found a family of molecules capable of inhibiting the virus and reaching the lungs, he says. The first of these molecules is Raloxifene.
“Computers always generate solutions,” Beccari says. “But not all of these simulations are good just because the computer says so.”
Beccari says the platform provides scientists with much more information than they can easily obtain from a two-dimensional format. This ultimately accelerates their ability to sift through the molecules that their supercomputers suggest as plausible candidates. In the future, he would like 3D platforms like Nanome to integrate with other platforms and tools. For example, his organization created an ultrafast algorithm to understand the coupling of molecules. According to him, it would be great to do both his computational and collaborative work within one space.
To move forward, the group will work on the design of Raloxifene-like drugs that improve their current skills against COVID-19. In this context, says Becarri, collaboration between scientists will be especially key. “In the age of artificial intelligence we believe people still rule,” he says.