Commercials for drugs all share one noticeable feature: a long list of side effects that the voice-over must read. The list sometimes can be longer than the rest of the ad, observes Denise Okafor, a biochemist at Pennsylvania State University. “And that is because these drugs won’t just bind the target thing they’re supposed to bind and fix. They will bind other things and mess up other things.”

Okafor wants to solve this problem of small-molecule drugs acting on unintended targets. She hopes that by studying how small molecules and proteins interact, she and other chemists can eventually develop drugs with fewer side effects.

In our cells, proteins and the small molecules they bind, called ligands, have much more exclusive relationships than the ones chemists can currently utilize in the design of drug molecules. Nature has created very tight partnerships between ligands and their targets, but chemists “haven’t learned the rules to be able to do it” themselves, Okafor says.

Okafor develops powerful simulations of how proteins and ligands interact to create moving images that may teach us these rules. These simulations reveal protein dynamics that could help explain how natural ligands bind their targets more specifically than drugs can.

“I think simulations have been one of the few ways that you can study protein dynamics,” Okafor says. Experimental methods like nuclear magnetic resonance spectroscopy can show researchers how proteins move, but simulations are much less expensive, so researchers can run them more often, she says.

Okafor’s laboratory focuses on nuclear receptors, a superfamily of proteins called transcription factors. When activated by ligands, these proteins regulate gene expression involved in different bodily processes, including metabolism, reproduction, and development.

In a recent publication, her team characterized how one of these nuclear receptors, called farnesoid X receptor (FXR), changes its conformation when a ligand binds to it. FXR is a drug target for metabolic diseases like type 2 diabetes and nonalcoholic steatohepatitis. Current drug candidates that bind FXR have side effects—they elevate cholesterol levels, lower high-density lipoprotein levels, and cause itchy skin.

When a ligand binds a nuclear receptor like FXR, the protein doesn’t activate the expression of just one gene but many, which can cause side effects. Currently, it is impossible to predict which genes will be activated or repressed when a drug binds FXR. By studying how ligands change FXR’s conformation and function, Okafor hopes to be able to make those predictions and create drug candidates with fewer side effects.

Okafor didn’t start her career studying protein-ligand interactions. As a graduate student in Loren Williams’s lab at the Georgia Institute of Technology, she studied RNA under conditions like those on Earth when life first appeared. Today, magnesium cations help certain RNA molecules fold and catalyze reactions. But when life first appeared, RNA likely had a different metal partner. During that period, iron was much more common in its Fe²⁺ oxidation state because oxygen levels were low. Scientists hypothesize that when photosynthetic organisms started to thrive, an event known as the great oxidation event depleted free Fe²⁺, and Mg²⁺ filled in the gap in RNA chemistry.

As a graduate student, Okafor found that substituting Mg²⁺ with Fe²⁺ improved the ability of some RNA molecules to catalyze reactions, suggesting that these RNAs once preferred Fe²⁺ as a partner.

Okafor was a leader on the iron project, and Williams saw that “she has a certain calmness and a kind of perseverance. She’s quiet but relentless.”

That perseverance, along with impactful mentors, got her through the hardest challenge in her career.

In graduate school, Okafor failed her qualifying exam, which she describes as feeling like a potential “death sentence” for a PhD student. “I remember at that point feeling very lost about what was next,” she says. She started questioning what she thought about herself and her abilities.

But with the help of mentors and faculty, Okafor dusted herself off and tried the exam again. “Even though all the vibes were negative, there were a handful of faculty members that were very intentional about being encouraging,” she says.

Okafor hopes to pass that resiliency in the face of a challenge onto others. “I’ve been very intentional about people who I’m interacting with, and just trying to keep them going,” she says. “You never know when someone needs to hear it to keep going.”