Angewandte Chemie International Edition
Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (23), 4459 - 4463
Molds for Molecules
Molecular imprints in polymers as reaction vessels
for pharmaceuticals research
Materials with the tiniest of cavities, which can take up other molecules as "guests", play a meaningful role in science and technology. A particularly interesting process for the synthesis of materials with precisely fitted cavities is known as molecular imprinting. This process involves the use of the molecules that are intended as future guests as templates; in their presence, individual building blocks are cross-linked to form a polymer. After the templates are removed, the resulting polymer contains cavities of the desired shape and size, and can be used for the precise separation of substances, as a catalyst, or as a sensor, for example. But molecular imprinting can do more, as a Swedish research group led by Klaus Mosbach has now shown. This technique can be applied to the search for specific pharmaceutical agents, because drugs must fit exactly, like a key in a lock, into the binding site of the biomolecule they are meant to affect. The outer structure of the drug thus plays a very important role.
The target of the first test runs was an inhibitor for the enzyme kallikrein, which participates in certain hormonal control systems. With the help of a previously known kallikrein inhibitor as the template, the researchers prepared a polymer with the corresponding cavities. The cavities act as tailored "molecular reaction chambers": they enable the coupling of two molecular building blocks - but only when the resulting product fits nicely into the chamber. These products then also fit into the binding site of the enzyme and thus act as inhibitors.
Mosbach and his team then went a step further and used - without the detour through a polymer - the binding site of the enzyme kallikrein itself as a reaction chamber. This direct method also led to reaction products that were inhibitors.
"Our methods make it possible to look for inhibitors, even if the structure of the enzyme is not known," is how Mosbach explains the advantages over classic screening methods. The polymer variation delivers very stable, reusable "reaction chambers", and allows the use of a wide variety of building blocks and reactions. The admittedly less stable direct variation has the advantage of working without a previously known inhibitor.