This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A square peg doesn't fit a round hole. But what if the peg could change the shape of the hole?
A newly developed drug molecule can do something surprisingly similar when binding to its target protein, according to a University at Buffalo-led study published Tuesday (Sept. 15) in Angewandte Chemie International Edition. The molecule, an inhibitor designed to block activity, initially clashed with a flexible loop in the structure of a protein implicated in cancer and known as p38 delta. This clash would normally hinder binding, but it instead caused the loop to change shape and wrap around the molecule, creating an unusually snug fit.
The molecule represented a 12,000-fold improvement in selectivity for p38 delta and was 110-fold more potent than previously available compounds. "Typically, you design a molecule to fit the target. Here, we designed a molecule that makes the target adapt to it," says corresponding author David Heppner, Ph.D., associate professor of chemistry in the UB College of Arts and Sciences.
The findings could provide a starting point for developing a new drug while also inspiring broader drug-design strategies that exploit similar structural features. "Instead of treating a target protein's structure as something to work around, we can think about how to make that structure work for us," Heppner says. The work was done in collaboration with Stefan Laufer, Ph.D., professor of pharmaceutical and medicinal chemistry at Tübingen University in Germany.
It was supported by the National Institute of General Medical Sciences, part of the National Institutes of Health, and the German Research Foundation. p38 mitogen-activated protein kinases are a family of proteins involved in regulating cellular activity. They are also notoriously difficult for drug molecules to bind to. Seidler synthesized several drug molecules to bind to these kinases as a Ph.D. student in Laufer's lab at the University of Tübingen.
One molecule stood out for being exceptionally selective for p38 delta, but exactly why it was so selective remained unclear. Then, as a Fulbright fellow in Heppner's lab at UB, Seidler conducted structural studies on the molecule. X-ray crystallography revealed that the molecule was causing p38 delta to change shape around it.
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