Scientists are always looking for better ways to design drugs that can fight tough diseases like lung cancer and COVID-19.
One group of drugs showing a lot of promise is called targeted covalent inhibitors (TCIs).
These are small molecules that can attach themselves permanently to specific proteins inside the body, shutting them down with great strength.
For a long time, researchers believed that the faster these drugs latched onto their protein targets, the better the drug would be.
This “inactivation efficiency rate” has been a key measure of how promising a drug might be.
But a new study from the University at Buffalo shows that speed isn’t everything.
The scientists discovered that while making TCIs faster did make them more powerful at first, this improvement quickly reached a ceiling.
Beyond a certain point, increasing speed no longer made the drug more effective.
In other words, once the drug was “fast enough,” extra speed didn’t help and could even confuse researchers into picking the wrong drug candidate.
This finding, published in the Journal of Medicinal Chemistry, highlights the need for a more balanced way of designing TCIs.
Instead of focusing only on speed, drug developers should also pay close attention to other factors, such as how selective a drug is—meaning how well it binds to the intended protein without hitting other, unrelated proteins in the body.
David Heppner, Ph.D., the lead researcher and professor of medicinal chemistry at UB, explained that relying only on the speed measure could easily lead scientists down the wrong path.
“If you simply followed the inactivation efficiency rate, you could end up selecting the wrong compound,” he said.
“We want to give drug developers an additional check on how to figure out the best compound before they get too far down the road.”
To test their theory, the team studied 14 advanced molecules designed to target a protein called EGFR. This protein helps cells grow, but when mutated, it can cause cells to grow uncontrollably and lead to cancer. TCIs have already been successful in blocking mutated EGFRs, making it the perfect case study.
The results showed that once TCIs reached a certain binding speed, their ability to stop the cancer-related protein didn’t improve further.
Even worse, some molecules that looked strong when judged only by speed turned out to be poor choices when tested in real cellular systems. This included a metabolite of an already approved drug, which slipped through the cracks when speed was the only measure.
To avoid this problem, the researchers suggest a two-step approach to designing TCIs. First, work on increasing binding speed until the molecule reaches a reasonable level. Then, instead of pushing for more speed, focus on other qualities such as selectivity. This balance can help scientists make smarter choices early in the drug discovery process, saving both time and money.
“Drug discovery is hard,” Heppner said. “Making good decisions early on is really important. Sometimes that means going back to the drawing board, as we did in this study, to find a more effective workflow.”
By slowing down and taking a broader view, researchers believe they can develop stronger, safer, and more effective drugs for diseases like cancer and COVID-19.
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