Drug discovery by dynamic combinatorial libraries

Dynamic combinatorial chemistry is a supramolecular approach that uses a self-assembly process to generate libraries of chemical compounds. Spontaneous assembly of the building blocks through reversible chemical reactions can, in principle, encompass all possible combinations.Addition of a target molecule to a dynamic combinatorial library (DCL) creates a driving force that favours the formation of the best-binding constituent — a self-screening process that can, in principle, greatly accelerate the identification of lead compounds for drug discovery.The generation of DCLs can essentially be accomplished using any type of reversible physical or chemical mechanism, as long as the respective interconverting states can be properly controlled and the final products identified. For drug discovery, it is also important that the reaction mechanism is compatible with biological targets.For a DCL to be efficiently produced, the building blocks need to fulfil several important characteristics. First, they must possess functional groups that can undergo reversible exchange. Second, they must cover as completely as possible the geometrical and functional space of the potential target. Third, these recognition groups need to be organized geometrically for optimal binding to occur.Three approaches to DCL generation and screening have been developed, which have a common first reversible generation step, but differ in the screening/selection phase:Adaptive DCLs: generation of the DCL is done in the presence of the target, resulting in amplification of the best-bound species, so that screening takes place simultaneously in the same compartment.Pre-equilibrated DCLs: generation of the DCL is achieved under reversible conditions, and the identification/screening is done under static conditions. No amplification can take place in this case, but this type of protocol is useful when working with sensitive biological target species that are unavailable in large amounts.Iterative DCLs: Generation of the DCL is achieved in one compartment under appropriate conditions, then in a subsequent step, members of the DCL are allowed to interact with the target species, either in the same reaction chamber or separately. Unbound species are then re-transferred to the reaction chamber, re-scrambled, and again allowed to interact with binding site. After several rounds, the accumulated active species can be analysed.