Computer models speed UCSF scientists toward psychiatric drug discoveries

Computer models speed UCSF scientists toward psychiatric drug discoveries

For decades, scientists have wanted to be able to study dopamine receptors one by one. The brain’s dopamine receptors are responsible for a variety of behaviors, such as reward seeking, and are also involved in psychiatric illnesses like schizophrenia. There are five types of dopamine receptors, and psychiatric drugs usually affect multiple receptors at once, often producing debilitating or even dangerous side effects.

When UC San Francisco postdoctoral scholar Anat Levit, PhD, embarked on her scientific career just over ten years ago, scientists were limited to studying neurotransmitter receptors by testing potential ligands—molecules that bind to receptors—in small batches, either in animal models or petri dishes, or using early virtual screening methods.

But today, as a researcher in the lab of Brian Shoichet, PhD, a faculty member in the School’s Department of Pharmaceutical Chemistry, Levit can virtually test hundreds of thousands to millions of molecules at a time on individual receptors, clearing the way for faster basic science and drug discovery.

Visualization of structure of the D4 receptor, bound to the antipsychotic drug nemonapride. Animation by Anat Levit, PhD (UCSF)

In work recently published in Science, Levit, Shoichet, and a team of scientists in Bryan Roth’s lab at the University of North Carolina-Chapel Hill (UNC) produced the first ever high-resolution map, or crystal structure, of a single type of dopamine receptor, D4, and used that structure to identify a specific ligand for the receptor. Impressively, the group went from solving the crystal structure of D4 to discovering a specific ligand in just one year.

Pushing the envelope

“Most dopamine receptor drugs are very dirty drugs that hit a bunch of different dopamine receptors,” said Levit. “We're not trying to find another dopamine ligand that does the same thing. We're trying to push the envelope and find chemicals that are different from what's out there.”

Using computational approaches that helped the Shoichet Lab discover a potentially safer opioid treatment last year, Levit virtually screened 600,000 chemicals to see if any would preferentially fit into the crystal structure of D4 that the UNC team had mapped. Once a few candidate molecules were identified in Levit’s virtual screen, the Roth Lab at UNC would test them.

Levit

Anat Levit, PhD, is a postdoctoral scholar in the Shoichet Lab in the Department of Pharmaceutical Chemistry, UCSF School of Pharmacy.

“We chose the compounds, they tested them, and whatever hit came back to us,” said Levit. “We would try to optimize the compounds and then send them back.”

Many potential drug molecules take more than a decade to develop, but in just one year, the group used this approach to hone in on one molecule, UCSF924. The molecule not only binds to D4 and activates it, but also leaves other receptors untouched, paving the way for targeted treatments of psychiatric disorders that may boast fewer side effects than available drugs. The compound is now being made available for purchase by Sigma-Aldrich, giving scientists worldwide the ability to probe the function of D4 for the first time.

While these findings haven’t produced a novel drug for treating psychiatric illness yet, Levit is excited about their implications. After all, she is making progress on the same questions she started to investigate early in her career. “I have a masters in genetics, with a focus on schizophrenia and bipolar disorder,” she said. “Now, I’m working on antipsychotic targets like D4, work which may lead to new treatments for these conditions.”

Read more:

Key Psychiatric Drug Target Comes Into Focus
 


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.

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