Scientists, including one of Indian origin, have created a new drug that blocks pain without triggering potentially deadly side effects of current prescription painkillers.
Researchers, including Aashish Manglik from Stanford University, custom-engineered the drug from scratch, using computational techniques to explore more than four trillion different chemical interactions.
They used the atomic structure of the brain’s “morphine receptor” to develop the drug candidate that blocked pain as effectively as morphine in mouse experiments, but did not share the potentially deadly side effects typical of opioids.
The drug did not interfere with breathing – the main cause of death in overdoses of prescription painkillers as well as street narcotics like heroin – or cause constipation, another common opioid side effect, researchers said.
The drug also appears to side-step the brain’s dopamine-driven addiction circuitry and did not cause drug-seeking behaviour in mice.
More research is needed to confirm that the drug is safe and effective in humans, the scientists said.
Much of drug discovery begins by taking a successful drug like morphine and tweaking its structure to get rid of side effects while maintaining its primary function. The new study took a different, much more radical approach.
“We didn’t want to just optimise chemistry that already existed. We wanted to get new chemistry that would confer completely new biology,” said Brian Shoichet, a professor at University of California, San Francisco in the US.
The atomic structure of the mu-opioid receptor, the brain’s “morphine receptor,” which was recently deciphered by 2012 Nobel laureate Brian Kobilka, a professor at the Stanford University School of Medicine.
With this structural information in hand, researchers turned to a computational approach called molecular docking.
In a two-week period, they performed roughly four trillion “virtual experiments” on a computer cluster, simulating how millions of different candidate drugs could turn and twist in different angles to find those configurations that were most likely to fit into a pocket on the receptor and activate it.
They also strove to avoid molecules that could stimulate beta-arrestin2, part of a biological pathway linked to the respiratory suppression and constipation typical of other opioids.
This led to a short-list of 23 candidate molecules. These were tested in the real world to identify the most potent one among the candidate drugs.
Researchers, including those from Friedrich-Alexander University Erlangen-Nurnberg in Germany, then optimised this compound’s chemical efficacy 1000-fold.
This approach succeeded in producing a molecule that the researchers called PZM21, which is chemically unrelated to existing opioid drugs. The research was published in the journal Nature reports PTI.