Scientists have designed a promising new painkiller that appears to separate the powerful pain dulling effects of synthetic opioids from side effects that include physical dependence, constipation, and potentially fatal respiratory depression.

To find the new drug--named PZM21 and detailed in a paper published today in Nature--a research team at UCSF’s School of Pharmacy simulated some four trillion different chemical interactions between the brain’s “morphine receptors,” and a virtual library of close to 4 million commercially available drug compounds. Choosing the best candidates, they then worked in collaboration with researchers from three other institutions to develop a compound that functioned in the way they hoped, after testing it in mice.

“Opioids can cause respiratory depression--that’s why people die, because they stop breathing,” says Brian Shoichet, a professor of pharmaceutical chemistry at UCSF’s School of Pharmacy and co-senior author on the paper. “Our hope was to come up a molecule that doesn’t have those effects.”

The scientists have raised venture capital funds from Kleiner, Perkins, Caufield and Byers to start a new company called Epiodyne, that will seek to develop the painkillers.

The finding is just the latest promising development in the ongoing effort to separate the pain numbing effects of opioids from their potentially deadly and addictive side effects—an effort that has taken on new urgency as opioid-related deaths and addiction in the United States reach epidemic proportions. (See “The Painkillers that Could End the Opioid Crisis”). A number of efforts are underway to develop a new painkiller without side effects, including a similar compound that’s currently being tested in humans.

Brian Kobilka, a Stanford University Nobel Laureate, is among the researchers behind the drug discovery.

An estimated 100 million Americans are afflicted with chronic pain. Up to 8 percent of patients prescribed narcotic painkillers for chronic pain will become addicted, according to the National Institute of Drug Abuse. In 2014, the number of deaths from opioid overdoses in the United States topped 18,000, about 50 a day—more than three times the number in 2001. And that doesn’t even take into account painkiller addicts who have turned to heroin to soothe their cravings. Officials at the Centers for Disease Control and Prevention recently compared the scale of the problem to the HIV epidemic of the 1980s.

The Nature paper, produced by scientists at UC San Francisco, Stanford University, the University of North Carolina, and the Friedrich-Alexander University Erlangen-Nürnberg in Germany, grew out of a years-long collaboration between Shoichet and Brian Kobilka, a Stanford University Nobel Laureate, Bryan Roth, a leading expert in opioid pharmacology, and Peter Gmeiner, a leading medicinal chemist.

The findings showcase the power of two key innovations that make it easier to develop new drugs. In 2007, Kobilka developed a new method that for the first time allowed scientists to map the precise atomic structure of a class of proteins in the brain known as G protein-coupled receptors (GPCRs). (In 2012, Kobilka’s innovations won him the Nobel Prize). GPCRs straddle the inside and outside of the cells and play a key role in the ability of brain cells to respond to biochemical signals emanating from elsewhere in the body—including the nerve impulses that make us feel pain.

Shoichet, meanwhile, has been working for almost three decades to build a computer program capable of simulating the way that different kinds of drugs interact on the molecular level with the brain. At the time of the analysis for the Nature paper, Shoichet’s computer program included a database with the chemical structures of between three and four million commercially available drugs.

Shoichet and Kobilka have been collaborating since 2007, when the Stanford researcher first developed his new techniques for mapping GPCRs. So when one of Kobilka’s graduate students, Aashish Manglik, used his methods to, for the first time, map the atomic structure of the receptors activated by opioids, it seemed an ideal opportunity.

Opioids, from OxyContin to heroin and morphine, work their magic by binding to what are known as MU receptors at the junctions where nerve cells meet. The binding reduces the ability of these cells to fire. So when nerve fibers at the periphery of the body send pain signals up to the brain for processing, the neurons that would normally make us feel this pain don’t respond.

But MU receptors aren’t located simply in the centers of the brain that detect pain. They are also found at other junctions all around the body in areas that have nothing to do with registering pain. Thus opioids can cause a wide number of side effects by exerting their influence in other parts of the body.

The challenge has been to find novel drug compounds that activate the proteins that numb pain without activating proteins that lead to the side effects. Working with another graduate student in Shoichet’s lab, Manglik programmed the database to simulate the way different drugs might interact with the receptor, in the hopes of finding one that did not produce unwanted side effects, which is what PZM21 appears to do.

“The virtual screening technology really pulled this out of a 4 million compound haystack,” says Stanford’s Kobilka, a co-author on the paper.