Understanding bound-state dynamics can guide COVID-19 drug discovery
DOI: 10.1063/10.0046164
Understanding bound-state dynamics can guide COVID-19 drug discovery lead image
The 3C-like protease (3CLpro) enzyme is vital for viruses’ ability to replicate, including coronaviruses. Some antiviral drugs work by inhibiting 3CLpro — for example, this is how nirmatrelvir/ritonavir (Paxlovid) targets the COVID-19 virus.
To better understand the way these drugs work, De Falco et al. studied how nirmatrelvir 3CLpro-inhibitors bind with the enzyme 3CLpro, uncovering previously unknown dynamics.
“Designing new drugs when the old ones don’t work anymore is based on what we know about how the drug binds to its target, and how we could modify that design to make better drugs,” said author Theresa Ramelot.
Using fluorine-19 nuclear magnetic resonance (19F NMR), the researchers found 3CLpro-inhibitor complexes slowly convert back and forth between two states, changing how they interact with 3CLpro. These dynamics were invisible to previous techniques, which study proteins in environments that suppress their motion.
Though the atomic nature of the motion is still poorly understood, the dynamics are fundamental to the way the proteins work. By tapping into these states, chemists can modulate a drug’s binding affinity to make more potent medications. Moreover, because 3CLpro-like enzymes exist in many different viruses, how they bind and what inhibits them is widely applicable beyond just coronaviruses.
“These are molecules that are actually being used in people,” said author Gaetano Montelione. “Millions of doses of this drug are being taken.”
The researchers do not know whether these dynamics play a role in drug safety, but they noted the importance of gathering as full a picture of 3CLpro systems as possible. Their work also demonstrates 19F NMR’s utility in studying slow drug-enzyme interactions, which can be used to monitor and improve other antiviral medications.
Source: “Slowly-exchanging bound states of SARS-CoV-2 3CLpro-inhibitor complexes revealed by 19F NMR,” by Anna De Falco, Ben Shurina, Rebecca Greene-Cramer, Theresa A. Ramelot, and Gaetano T. Montelione, Structural Dynamics (2026). The article can be accessed at https://doi.org/10.1063/4.0001210 .
This paper is part of the Tribute to a Lifelong Innovator: John Markley and the Evolution of Biomolecular NMR Collection, learn more here .
