New twist on chemistry method reveals a treasure trove of novel protein targets for small-molecule drugs
Improving upon an approach they developed two years ago, a bicoastal team of chemists add new power to drug discovery efforts.
October 31, 2019
LA JOLLA, CA, and JUPITER, FL — The world of possibility for new and better small-molecule medicines has widened significantly with the latest discovery from chemists at Scripps Research. A team led by Christopher Parker, PhD, and Ben Cravatt, PhD, found a way to quickly identify proteins that can interact with drug candidates directly in living cells.
The findings, published in Nature Chemistry, provide a valuable new approach to power drug discovery across a range of disease areas including cancer, immunology and neurobiology.
“Even with all of the advances in drug development and medical care, only a fraction of our 20,000-or-so human proteins are targeted by drugs today,” says Parker, assistant professor of chemistry on Scripps Research’s Florida campus. “We found a way to survey the landscape of proteins that exist in human cells and identify ‘druggable’ areas that are still flying under the radar of modern medicine.”
The majority of all medicines today are what’s known as “small molecule” drugs, a category encompassing everything from aspirin to antidepressants. Usually taken by mouth, these drugs exert their effect by acting on proteins in the body. Some may stimulate a cellular process that creates a desired effect; others may block a process that’s causing trouble. Aspirin, for example, inactivates a type of protein that that causes inflammation.
But as Parker notes, only a small share of human proteins is currently considered “druggable.” Roughly 6,000 proteins are known to be involved in human disease, yet a scant 600 have drugs targeting them.
As the team set out to map new and better drug targets, they had a favorable starting point. They were able to build upon their landmark study in Cell from two years earlier, in which they introduced a new process using chemical “probes,” which are essentially tiny fragments of small-molecule drugs that bind to a protein partner. This study revealed thousands of new protein-fragment interactions in human cells and showed that these interactions could be advanced to small molecules that modulate protein function. The research was eye-opening, but there was a catch: The scientists weren’t always able to easily discern exactly how selective or “druggable” these interactions were, Parker says.
The new research, led by Parker and Yujia Wang, a graduate student in the Cravatt lab, presents a much faster way to find and confirm promising new drug targets. The team built a library of specialized probes that would leave little room for mystery. They did this by creating pairs of drug fragments that were mirror images of one another—and therefore, not superimposable—but otherwise identical.
“By minimizing the structural differences between the probes, we were able to more efficiently home in on uniquely druggable protein targets,” Parker says.
Finding unique targets is key, as drug developers want a medicine to only interact with a specific protein to control the outcome of interest, and not create undesirable side effects. “It’s an expedited way to map these types of targets and gain confidence that you’re hitting druggable sites,” he says.
By directly comparing the protein interactions of each mirror image, the team was able to cancel out interactions that weren’t as useful for drug discovery. For example, if both members of a pair stuck to many of the same proteins, but only one protein elicited a preference for one of the mirror images, it was a clear sign of a promising druggable site.
The study tested a set of eight mirror-image probes on human white blood cells; these cells are central to immune response, making them of special interest for medicine. However, future studies can test out different probes on a wide range of cells—the possibilities are seemingly endless.
“There are a number of exciting directions this can take us next,” says Parker. “We want to figure out ways to find as many druggable proteins as we can.”
Authors of the study, “Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs,” include Yujia Wang, Melissa M. Dix, Giulia Bianco, Jarrett R. Remsberg, Hsin-Yu Lee, Stefano Forli, Christopher G. Parker and Benjamin F. Cravatt of Scripps Research; Marian Kalocsay and Steven P. Gygi of Harvard; and Gregory Vite, and R. Michael Lawrence of Bristol-Myers Squibb.
For more information, contact press@scripps.edu