What if we could design powerful drugs without unwanted side effects?

May 19, 2020

Psychedelics such as LSD and magic mushrooms have proven highly effective in treating depression and post-traumatic stress disorders, 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?" asks Ron Dror, an associate professor of computer science at Stanford. Dror's lab is developing computer simulations 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. LSD and other psychedelics are molecules that attach to GPCRs, as are about a third of all prescription drugs, including antihistamines, beta blockers and opioids. 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 causes multiple simultaneous changes in the cell, some beneficial and some dangerous.

By comparing simulations of a GPCR with different molecules attached, Dror's team was able to pinpoint how a drug molecule can alter the GPCR's shape to deliver beneficial effects while avoiding side effects, something that had remained mysterious until now. Based on these results, the researchers designed new molecules that indeed caused 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.

Today, researchers typically test millions of drug candidates - first in test tubes, then in animals and finally in humans - hoping to find the magic molecule that is both effective and safe, meaning that any side effects are tolerable. This massive undertaking typically takes many years and costs billions of dollars, and the resulting drug still often has some frustrating side effects.

The discoveries by Dror's team promise to allow researchers to bypass a lot 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 that these potential drugs will prove very safe and effective.

Postdoctoral scholar Carl-Mikael Suomivuori and former graduate student Naomi Latorraca led an 11-member team that included Robert Lefkowitz of Duke University, with whom Kobilka shared the Nobel Prize, and Andrew Kruse of Harvard University, Kobilka's former student.

"In addition to revealing how a drug molecule could cause a GPCR to trigger only beneficial effects," Dror said, "we've used these findings to design molecules with desired physiological properties, which is something that many labs have been trying to do for a long time."

"Armed with our results, researchers can begin to imagine new and better ways to design drugs that retain their effectiveness while posing fewer dangers," Dror said. He hopes that such research will eventually eliminate dangerous side effects of drugs used to treat a wide variety of diseases, including heart conditions, psychiatric disorders and chronic pain.
By Tom Abate

Stanford School of Engineering

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