The power of combinatorial chemistry<\/h4>\n

At the heart of this breakthrough lies combinatorial chemistry, which aims to produce as many molecular variants as possible from individual building blocks. The number of different molecules grows exponentially with each synthesis cycle and the number of building blocks combined.<\/p>\n

To identify active compounds within this vast molecular soup, the DEL method attaches a unique DNA sequence to each molecule, creating a readable barcode for every combination\u00a0 of building blocks. This allows researchers to test the entire collection for specific properties, such as the ability to bind to a particular protein, and then identify promising candidates using PCR techniques.<\/p>\n

While the concept of DEL has been around since the early 2000s, its practical application has been limited by chemical realities. The varying effectiveness of chemical linkages between building blocks led to the production of truncated variants, resulting in exponentially increasing impurities with each round of synthesis.<\/p>\n

Scheuermann\u2019s team has developed a solution to this problem by introducing a self-purifying mechanism. Their method couples the synthesis of molecules to magnetic particles and incorporates a second chemical coupling component that binds only to the last of the planned building blocks. This allows for the removal of all truncated molecules in a single washing step, ensuring that the final library contains only molecules with all the specified building blocks.<\/p>\n

Expanding the scope of drug discovery<\/h4>\n

The implications of this advancement are far-reaching. Not only does it allow for the handling of much larger libraries of several billion molecules, but it also enables the synthesis of bigger molecules consisting of five or more building blocks.<\/p>\n

\u201cBefore, we could search for small active substances that fit like a key into the lock of the active site of therapeutically relevant proteins, but now we can search for larger ones as well,\u201d Scheuermann noted. \u201cThese larger active substances can dock not only in a protein\u2019s active centres, but also to other specific areas of a protein\u2019s surface, for example, in order to prevent it from binding to a receptor.\u201d<\/p>\n

This expanded capability opens up new possibilities for drug development, potentially allowing researchers to target a wider range of proteins and cellular processes.<\/p>\n

The new DEL technology is not only poised to accelerate drug discovery but also holds promise for fundamental biological research. By enabling the identification of molecules that bind to specific protein surfaces, it could facilitate the labelling and examination of proteins in their cellular context.<\/p>\n

Moreover, this advancement could significantly contribute to major international research initiatives such as Target 2035, [2] which aims to find a specific binding molecule for each of the approximately 20,000 human proteins by 2035.<\/p>\n