New Data Method Revolutionizes Drug Discovery at Baylor College

Researchers at Baylor College of Medicine have introduced a groundbreaking data analysis method called COOKIE-Pro, aimed at enhancing drug development. Published in the journal Nature Communications, the study details a technique that assesses how covalent inhibitors interact with proteins across the entire proteome. This innovative approach allows for the simultaneous measurement of binding strength and reaction speed against thousands of potential targets, expediting the creation of more effective and safer therapeutics.

Covalent inhibitors, commonly used in drugs like aspirin and the cancer treatment ibrutinib, form strong, permanent bonds with their target proteins. According to Jin Wang, PhD, director of the Center for NextGen Therapeutics and corresponding author of the study, “This strength can be a double-edged sword; these drugs can also bind to unintended off-target proteins, potentially leading to unwanted side effects.” This highlights the necessity of balancing binding strength and reaction speed in drug design.

Overcoming Drug Development Challenges

Traditional methods have struggled to measure these parameters effectively across the proteome, creating bottlenecks in drug development. Hanfeng Lin, the study’s first author and a graduate student in Wang’s lab, noted the importance of obtaining a comprehensive view: “We needed to measure both affinity and reactivity, but doing it for one protein takes time, let alone thousands.” The COOKIE-Pro method provides a detailed map of drug interactions, revealing not only whether a drug binds off-target but also the extent and speed of that binding.

The method utilizes a specially designed “chaser” probe that attaches to protein-binding sites left unoccupied by the drug. The binding of this probe is then measured using mass spectrometry, allowing researchers to calculate both the binding affinity and the inactivation rate for numerous proteins simultaneously. This high-throughput approach enables the evaluation of thousands of potential drug interactions with unprecedented efficiency.

Validation and Future Implications

The research team validated COOKIE-Pro using two established drugs: spebrutinib and ibrutinib. Results indicated that spebrutinib is over ten times more potent against the off-target protein, TEC kinase, compared to its intended target, Bruton’s tyrosine kinase (BTK). For ibrutinib, COOKIE-Pro identified known off-targets and produced profiles consistent with previously published data, confirming the method’s reliability.

In an application of this high-throughput technique to a library of 16 covalent inhibitor fragments, the team generated thousands of profiles, demonstrating COOKIE-Pro’s capability to efficiently guide the early stages of drug discovery. Wang emphasized that the ultimate goal is rational drug design: “COOKIE-Pro allows us to separate intrinsic reactivity from true binding affinity. We can now help chemists prioritize compounds that are potent because they bind specifically to the right target, not just because they are broadly reactive.”

This advancement marks a significant step towards developing the next generation of highly selective and safer covalent medicines, potentially transforming therapeutic strategies in various medical fields.