Researchers from U.C. San Francisco, Stanford University, the University of North Carolina and the Friedrich-Alexander University Erlangen-Nürnberg have cooked up a new opioid drug candidate from scratch that they say can block pain without triggering the dangerous side effects of painkillers.
Their study was published this week in Nature showing the computational techniques that allowed them to explore more than four trillion different chemical interactions. They used a newly deciphered atomic structure of the brain’s “morphine receptor” to cook up a novel drug candidate from scratch, and it blocked pain as effectively as morphine in experiments using mice. The notable outcome was that the new drug did not share the “potentially deadly side effects typical of opioid drugs,” such as depressed breathing, constipation or drug-seeking behavior in the mice.
“Morphine transformed medicine,” said Brian Shoichet, PhD, a professor of pharmaceutical chemistry in UC San Francisco’s School of Pharmacy and co-senior author on the new paper. “There are so many medical procedures we can do now because we know we can control the pain afterwards. But it’s obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades.”
Shoichet says that, much of the drug discovery begins by taking a successful drug like morphine and tweaking its structure to try to get rid of side effects. The new study took a different, much more radical approach: “We didn’t want to just optimize chemistry that already existed,” Shoichet said. “We wanted to get new chemistry that would confer completely new biology.”
“With traditional forms of drug discovery, you’re locked into a little chemical box,” Shoichet said. “But when you start with the structure of the receptor you want to target, you can throw all those constraints away. You’re empowered to imagine all sorts of things that you couldn’t even think about before.”
Through their extreme computational approach, called molecular docking, they performed four trillion “virtual experiments” simulating how millions of drug candidates could morph and twist, and looked for the results that were most likely to fit into a pocket in the receptor and activate it. They found a short list of 23 potential candidate molecules, and ultimately created a molecule that they called PZM21, which is chemically unrelated to existing opioid drugs.
PZM21 appeared to dull pain by affecting opioid circuits in the brain only, with little effect the on opioid receptors in the spinal cord that mediate pain reflexes. No other opioid has such a specific effect, Shoichet said, calling it “unprecedented, weird and cool.”
Image courtesy of www.ucsf.edu