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Scientists have discovered a new way to advance drug discovery and diagnostics by targeting a part of the proteome (the complete set of proteins in an organism) that was previously thought inaccessible to drug development, often referred to as "undruggable" targets.

Proteins are the workhorse of the body and vital for drug discovery. When something goes wrong in diseases like cancer or diabetes, for example, it's because one or more proteins aren't working as they should. Drugs commonly bind to specific parts of these proteins to block harmful actions or boost beneficial ones.

Limits of traditional approaches

Currently, when searching for new medicines, researchers will look for proteins with stable, unchanging structures. However, this approach overlooks proteins with intrinsically disordered regions (IDRs), which make up more than 50% of the proteome. These proteins don't have a fixed shape, which makes it harder for researchers to target them. Consequently, science could be missing out on a vast array of potentially life-changing new medicines.

IDRs in proteins are thought to play crucial roles in normal cellular functions, as well as contributing to many disease processes. However, traditional approaches to targeting these flexible regions with antibodies are labor-intensive and often ineffective.

New technique

In a published in Science, researchers from the lab of Nobel Prize-winning chemist David Baker describe a novel technique called "logos." This system uses AI to design new molecules that can bind to these tricky sites.

So how does it work? Instead of creating a molecule that tries to fit into a pocket of an ever-changing protein, the binders designed by logos are their own pockets into which the targets fit. The researchers successfully designed these types of binders for 39 unstructured targets.

"Our computational design pipeline enables the design of binding proteins to arbitrary disordered peptides and proteins," wrote the researchers in their paper. "Although targeting disordered proteins has been a considerable challenge for traditional methods, we show that the disorder is an advantage: The designed binding protein drives the target sequence into a privileged binding-competent conformation."

Future possibilities

This groundbreaking approach means many more proteins could become targets for new medicines. This could help speed up research into diseases where proteins with IDRs are a significant factor, including cancers and neurodegenerative disorders such as Alzheimer's.

The success of this work is further proof that artificial intelligence and computational design are becoming essential tools for tackling seemingly intractable challenges in biology and medicine.

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