Virtual drug screening leads to new compounds to treat pain and depression

Chemical compounds developed by UCSF researchers could lead to a new generation of antidepressant and pain medications, offering relief with fewer side effects than current therapies.

The work, led by the UCSF School of Pharmacy’s Brian Shoichet, PhD, was detailed in separate papers published in the September issues of Nature and Science, respectively.

In both studies, Shoichet, faculty member in the Department of Pharmaceutical Chemistry, used the “docking” technique he pioneered to screen virtual libraries containing millions of molecules for candidate drugs that fit precisely into receptors of interest.

For the first study, Shoichet and longtime collaborator, Bryan Roth, MD, PhD, from the University of North Carolina, joined forces to develop new molecules that could activate 5-HT2A, a type of serotonin receptor known to be involved in a variety of psychiatric conditions. This receptor is activated by anti-depressants, like Prozac, and psychedelics, like LSD—which has also been shown in recent years to hold promise in treating depression.

The team built a library of 75 million novel compounds and virtually screened them for 5HT2A activity. With the help of colleagues from Yale University and Duke University, the group winnowed this library down to a handful that, in animal models, appeared to improve mood without causing hallucinations (in animals, psychedelics produce tail-twitching).

“The final molecules were 100 times more potent than what we started with, and in the animals they are much more potent than Prozac,” Shoichet told UCSF News. The anti-depressant benefits lasted for up to two weeks from just one dose, though they were not nearly as long-lasting as the benefits of LSD, he said.

In the second study, Shoichet worked with UCSF’s Allan Basbaum, PhD, and collaborators from Freidrichs Alexander University in Germany, the Chinese University of Hong Kong, and the University of Montreal, to create pain-relieving drugs that didn’t cause addiction or sedation. The group focused on compounds that activated alpha-2A, an adrenergic receptor, which Basbaum had recently identified as a promising target for new painkillers.

This time, Shoichet and his colleagues screened a virtual database of 300 million for those that activated alpha-2A and narrowed it down to just six molecules for testing in animals. They found that all six delivered pain relief without putting the animals to sleep or causing addictive behavior. And because these drugs target an adrenergic receptor, and not opioid receptors, they could, in theory, be used in conjunction with opioid drugs, reducing the amount of opioid needed to bring relief.

“If we can create a drug that works [to treat pain] in combination with a much lower dose of opiate, that would be the dream,” Shoichet told UCSF News. “The need for that is huge.”

More

LSD-Like Molecules Counter Depression Without the Trip (UCSF News)

Non-Opioid Compounds Squelch Pain Without Sedation (UCSF News)