Forty years of combinatorial technology.

Combinatorial technology has been facilitating the synthesis and screening of large molecular libraries containing millions of organic compounds ever since its introduction 40 years ago. It has changed the paradigms of pharmaceutical research from focusing on single compounds to focusing on immense collections of compounds. It inspired the development of dynamic combinatorial libraries, fragment-based drug discovery and virtual library screening. Combinatorial technology was revitalized by the development of DNA encoding. Amplification of DNA oligomers plus next-generation sequencing has made it possible to successfully screen billions of compounds in a single process.

Combinatorial technology revitalized by DNA-encoding.

Combinatorial chemistry invented nearly 40 years ago was welcomed with enthusiasm in the drug research community. The method offered access to a practically unlimited number of new compounds. The new compounds however are mixtures, and methods had to be developed for the identification of the bioactive components. This was one of the reasons why the method could not providethe expected cornucopia of new drugs. Among the different screening methods, two approaches seem to offer the best results. One of them is based on the intrinsic property of the combinatorial split and pool solid-phase synthesis: One compound forms on each bead of the solid support. Different methods have been developed to encode the beads and identify the structure of compounds formed on them. The most important method applies DNA oligomers for encoding. As a second approach in screening, DNA-encoded combinatorial libraries are synthesized omitting the solid support and the mixtures are screened in solution using affinity binding methods. Libraries containing billions and even trillions of components are synthesized and successfully tested, which led to the identification of a significant number of new leads.

Preparation of cherry-picked combinatorial libraries by string synthesis.

String synthesis [1-3] is an efficient and cheap manual method for preparation of combinatorial libraries by using macroscopic solid support units. Sorting the units between two synthetic steps is an important operation of the procedure. The software developed to guide sorting can be used only when complete combinatorial libraries are prepared. Since very often only selected components of the full libraries are needed, new software was constructed that guides sorting in preparation of non-complete combinatorial libraries. Application of the software is described in details.