Combinatorics: Chemistry with Big Numbers

As a result of the tremendous acceleration of automated compound screening for biological activity, the number of compounds to be tested has increased significantly. This has stimulated the development of automated parallel synthesis and combinatorial chemistry. Nature produces an enormous chemical diversity by combining either amino acids or nucleic acids to form polymers. These polymers fold in space to produce 3D arrangements. It has been estimated that the chemical space of organic molecules with up to 25 atoms other than hydrogen that meet the requirements for drug-like properties contains about 1027 conceivable candidates. There are 166.4 billion molecules in a systematically generated computational database with up to 17 C, N, O, S, and halogen atoms. Chemical reactions on solid supports, typically organic resins such as crosslinked polystyrene, follow a stepwise synthesis strategy for the sequential assembly of molecules on the solid phase. Complete yields and easy purification can be achieved, and product release from the solid phase follows in the final step. In order to generate multiple products on the solid support from reagent mixtures in a limited number of reaction steps, sophisticated synthetic strategies have been developed. Elaborate protocols have been established to monitor product formation, including the use of sophisticated chemical labeling techniques. DNA encoded libraries are increasingly being used as this technique does not necessarily require syntheses on resin. This greatly simplifies subsequent testing of the library in biochemical activity assays. Testing the biological activity of libraries of compounds generated by combinatorial chemistry on a solid support requires sophisticated protocols for library detachment and deconvolution. Taking into account the properties of the target against which the library will be screened, the design and selection of the building blocks used to synthesize the library are purposeful. Several protocols in which either the library substrates are immobilized on the solid phase or the reagents are immobilized and the library is developed in the solution phase have been developed, either for combinatorial chemistry or parallel synthesis. The target protein can be added to a mixture of reagents by reaction from click chemistry or equilibrium reactions in dynamic combinatorial chemistry. From a large number of possible reaction products, the protein binding pocket selects the best binder as a potent inhibitor or antagonist of the target protein. https://sn.pub/qhucur