November 17, 2019

Virtual View of Molecular Interactions

Dr. Zoran Radić, a UC San Diego scientific researcher, uses VR to explore treatments to a deadly nerve agent

By Antonie Boessenkool, California Business Journal.

For four decades, Dr. Zoran Radić, a professor at UC San Diego, has studied a key enzyme in the human nervous system called acetylcholinesterase, or AChE. This complex molecule, made up of thousands of atoms, is the target of deadly nerve agents like the one used against a former Russian spy last year.

For most of his career, Radić has analyzed AChE using traditional methods. But in the last three years, a virtual reality tool by San Diego company Nanome has allowed his research to leap forward. With Nanome’s VR tool, he can – virtually – manipulate AChE, study its interactions with other molecules, present his research in a more accessible and visible way, even collaborate with other researchers remotely in the VR space. In the future, Radić says, tools like Nanome’s VR will become essential to drug development companies, potentially cutting the time it takes to develop new treatments.

“The actual goal of every researcher in drug discovery, in structural biology, is to effectively be able to shrink oneself and get into that microscopic world in order to understand it,” he says. “That’s precisely what virtual reality is allowing us.”

With Nanome’s VR tool, Dr. Radic can - virtually - manipulate AChE, study its interactions with other molecules, present his research in a more accessible and visible way and collaborate with other researchers remotely in the VR space.

With Nanome’s VR tool, Dr. Radic can – virtually – manipulate AChE, study its interactions with other molecules, present his research in a more accessible and visible way and collaborate with other researchers remotely in the VR space.

Radić’s work focuses on structure-based drug design — that is, researching the architecture of large biological molecules — targets for drugs — to develop small molecules and drugs that are effective treatments. The large molecules he studies are vastly complex, made of 8,000 to 10,000 atoms. Using virtual reality allows him to see and handle the microscopic molecule up close.

Three years ago, Radić started searching for a virtual reality tool to use in his research. With Oculus Rift gear, he tried a program created by a scientist in Sweden. Though Radić could “see” the macromolecule in virtual reality, he couldn’t interact with it.

Steven McCloskey, CEO of Nanome, contacted Radić after learning of the professor’s interest in using VR for molecular research. McCloskey invited Radić to Nanome’s offices, then at UC San Diego, so Radić could take a look at their VR software then in development.

“What they had was already really impressive,” Radić says. “It looked much better than anything I had seen up to that point, anywhere, in terms of molecular visualization.” He discovered he could manipulate the molecule in virtual reality, isolate groups of atoms and highlight them with color and — importantly for potential drug discoveries — he could create new molecules to study interactions with the large molecule.

Radić now gives Nanome feedback on how to make the software more researcher-friendly. McCloskey refers to Dr. Radic as a “power user.”

Another advantage of Nanome’s tool, one that is key to Radić’s research of Russian nerve agents, is that it shows the variety of possible shapes a large molecule can take. Molecules aren’t static, and they change shape as they’re affected by energy and heat. Developing effective drugs depends partly on the molecule’s shape – finding places on the large molecule where small molecules drugs can attach. Nanome’s VR can find the best fit for a drug within the thousands of atoms making up the large molecule.

A-232, the nerve agent likely behind the attack on former Russian spy Sergei Skripal and his daughter Yulia Skripal last year in the United Kingdom, is one of the “Novichik” or “newcomer” chemical weapons the Soviet Union started developing almost 50 years ago.

A nerve agent works by fitting into a cavity on AChE and making a stable bond, though the agent usually leaves open some space in this cavity. That remaining space allows an oxime to work as treatment for victims of nerve agent attacks. An oxime can pry out the nerve agent from the cavity before it has bonded permanently to AChE.

But Radić discovered using Nanome’s VR technology, A-232 is different.

“The first impression was how well this whole molecule of toxin, of nerve agent, fits into the active center, or cavity, of the large target and fills it practically completely,” he says. That could make an oxime less effective as a treatment. It also means a new out-of-the-box approach is needed to create an antidote, he adds.

“That’s where we need to work now, on designing antidotes that will be different, obviously, from those that were approved to be efficient against other nerve agents,” he says. “We’ll have to create something new.”

Nanome says one of the benefits of its VR tool is that specialist researchers, say, structural biologists, can interact within the software with non-specialists at other locations. This type of collaboration might be the innovative approach that’s needed to create an A-232 antidote.

The exact structure of A-232 isn’t publicly known, but Radić believes he may have discovered its makeup, building on incomplete information about the structure released in 1992 by former Soviet chemist Vil Mirzayanov and using Nanome to analyze it virtually.

“There is more than 95 percent probability that what I’m modeling in Nanome is exactly what was used in U.K. last year.”

Radić and his colleagues are working on one approach, a “smart” antidote that can adapt its shape to its target. For an upcoming conference for the American Chemical Society, Radić plans to use VR imagery to communicate his research.

Radić foresees a time when Nanome’s VR could become an essential tool for drug research and development. Already, his pharmacy students are using Nanome’s VR tool in his classes. VR performance is advancing as costs of VR hardware are falling, which could lead to more researchers adopting VR as a research tool. But, Radić says, so far that adoption is happening only slowly.

Still, compared to the research tools he used at the beginning of his career, VR allows a completely new perspective, and new insights. “There is a significant and critical improvement in perception and ability to develop new biologically active molecules now as opposed to before.”

Copyright © 2019 California Business Journal. All Rights Reserved.

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  • Unbelievable article. Who knew this was possible. Great work gentlemen.

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