Reduced Medication Side Effects, Thanks to a Supercomputer

Newswise—Psychedelic drugs could be effective in treating psychiatric disorders such as depression and post-traumatic stress disorder, but medical use of these drugs is limited by the hallucinations they cause.

“What if we could redesign drugs to keep their benefits while eliminating their unwanted side effects?” asked Ron Dror, an associate professor of computer science at Stanford University. Dror’s lab is developing computer simulations using the world’s most powerful and smartest supercomputer for open science, the IBM AC922 Summit supercomputer at the Oak Ridge Leadership Computing Facility (OLCF), to help researchers do just that.

In an article published in Science, Dror’s team describes discoveries that could be used to minimize or eliminate side effects in a broad class of drugs that target G protein-coupled receptors, or GPCRs. GPCRs are proteins found in all human cells. Lysergic acid diethylamide (LSD) molecules and other psychedelics attach to GPCRs—but so do about a third of all prescription drugs, including medications for allergies, blood pressure, and pain. So important is this molecular mechanism that Stanford professor Brian Kobilka shared the 2012 Nobel Prize in Chemistry for his role in discovering how GPCRs work.

When a drug molecule attaches to a GPCR, it can cause multiple simultaneous changes in the cell. Some of these changes might contribute to a drug’s beneficial effects, but others can lead to less-than-desirable or even dangerous effects.

Using the OLCF’s Summit and a computing cluster at Stanford, the team compared computer simulations of a GPCR with different molecules attached. Dror’s team was then able to pinpoint how a drug molecule can alter the way a GPCR’s atoms are ordered. Changing the protein’s atomic arrangement affects the protein shape and can allow a drug molecule to deliver beneficial effects without side effects—something that has remained mysterious until now. Based on these results, the researchers designed new molecules that were shown computationally to cause beneficial changes in cells without unwanted changes. Although these designed molecules are not yet suitable for use as drugs in humans, they represent a crucial first step toward developing side-effect-free drugs.

The discoveries by Dror’s team promise to allow researchers to bypass much of that trial-and-error work so that they can bring promising drug candidates into animal and human trials faster and with a greater likelihood of success.

Dror hopes that such research will eventually eliminate the dangerous side effects of drugs used to treat a wide variety of diseases, including heart conditions, psychiatric disorders, and chronic pain.

 

Read the full press release on Newswise.

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