Abstract
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.
Highlights
Combinatorial Technology had been invented by the author of this article almost 40 years ago
The invention was described in a document notarized in 1982.1 Combinatorial technology is defined in the document as follows: “The essence of the proposal is that instead of one by one synthesis of peptides, peptide mixtures should be prepared containing several hundred or several thousand peptides in approximately 1 to 1 molar ratio, and these peptide mixtures should be submitted to screening tests
Using the solid phase split and pool synthesis, no more compounds can be synthesized than the number of beads in the solid support
Summary
Combinatorial Technology had been invented by the author of this article almost 40 years ago. The use of compound mixtures in the syntheses has a serious disadvantage: The structure of the produced compounds is unknown and finding a bioactive compound in a mixture of millions of peptides seemed to be similar to the task of finding a needle in a haystack To overcome this difficulty, different deconvolution methods had been introduced. In synthesizing organic OBOC libraries, organic solvents are commonly used, while in building the DNA oligomers, an aqueous medium is needed.[27] To solve the problem, Paegel et al offered a method in which the steps of compound synthesis are executed in the organic solvent, while the parallel building up of the DNA-encoding oligomers is carried out in an aqueous solution.
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