Shoichet co-led research develops safer, potentially less addictive painkiller

Research co-led by UCSF School of Pharmacy faculty member Brian Shoichet, PhD, has developed a new opioid drug candidate that blocks pain as effectively as morphine in mice, without triggering dangerous side effects, and also apparently without the addictive properties of current prescription painkillers.

As detailed in a paper published online in Nature on August 17, 2016, the newly engineered therapeutic lead did not depress breathing, which is the main cause of death in overdoses of both prescription painkillers and street narcotics—deaths that have more than quadrupled since 1999. Yet the new molecule retains vital pain relief.

“Morphine transformed medicine,” said Shoichet, co-senior author of the new study. “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.”

The new compound also appears to sidestep the brain’s dopamine-driven addiction circuitry and did not cause drug-seeking behavior in mice. More work is needed to establish that the new drug lead is truly nonaddictive and to confirm that it is as safe and effective in humans as in the study’s rodents, the authors say.

The finding was made possible by combining a computational drug discovery technique called molecular docking—pioneered at the School in the 1980s by Shoichet’s mentor, emeritus faculty member Tack Kuntz, PhD—with the atomic-level structure of the brain’s mu-opioid receptor. That receptor structure was recently deciphered by paper co-senior author and 2012 Nobel laureate Brian Kobilka, MD, a faculty member at the Stanford University School of Medicine.

Instead of tweaking the morphine molecule to reduce its side effects, “We wanted to get new chemistry that would confer completely new biology,” said Shoichet.

“With traditional forms of drug discovery, you’re locked into a little chemical box,” he 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.”

Brian Shoichet

Schematic diagram of computer-based molecular docking process used to screen for new compounds that selectively bind to the mu-opioid receptor without triggering dangerous side effects. Candidates were further optimized and tested in mice.

Over a two-week period, researchers performed roughly four trillion virtual experiments on a UCSF computer cluster, simulating how millions of different molecules could turn and twist in millions of different angles to find those configurations that were most likely to fit into a pocket on the receptor and activate it. They sought to avoid structures that could stimulate a part of a biological pathway linked to breathing suppression and constipation typical of other opioids.

This led to a short list of 23 candidate compounds mostly likely to activate the mu-opioid receptor in the way the researchers wanted. Ensuing analysis, optimization (including a 1,000-fold increase in chemical efficacy), and animal testing by the laboratories of co-senior authors Bryan Roth, MD, PhD, of the University of North Carolina School of Medicine, and Peter Gmeiner, PhD, of the Friedrich-Alexander University Erlangen-Nürnberg in Germany, led to the engineering of a molecule dubbed PZM21, which is chemically unrelated to existing opioid drugs.

The Shoichet Lab is based in the School’s Department of Pharmaceutical Chemistry. The Nature study was co-lead-authored by Henry Lin, a former graduate student in the lab who is now a principal scientist at the Janssen Pharmaceutical Companies of Johnson & Johnson.

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