1. Field of the Invention
The present invention relates to a method for synthesizing an encoded molecule. Furthermore the invention pertains to a method for identifying a molecule with desired characteristics and in certain aspects to a library of encoded molecules obtained by a method according to the invention.
2. Description of the Related Art
Methods are desired for increasing the efficiency of production and screening of chemical libraries with the purpose of generation and isolation of new compounds that can be used for applications in medicine, agriculture and other areas. Active molecules, for example for use in medicine, have been identified by screening of natural materials (such as plant extracts) or chemical libraries of synthesised molecules in assays that identify molecules with the desired properties. The outcome of such screens usually only is low affinity leads, i.e. molecules that are identified in the assay, (e.g. by binding to a target molecule or by another function), but which have insufficient affinity and specificity for the target. Further improvement of the leads is therefore required, which can be done empirically or by chemical design. In either case, the process of lead optimisation is time-consuming and expensive and in many cases it does still not provide molecules with sufficient affinity and specificity for the target molecule to exert the desired function with high efficiency and without unwanted reactions to occur. Methods are required that increase the size of the compound libraries, in order to increase the diversity in the pool of molecules that is used for screening, and as the size of the libraries increase improved methods are required to identify the molecules that have the desired properties in the screening assay.
DNA-encoding of compounds provides a means to perform more efficient screens or selections where the isolated compound-DNA complexes can be identified at the end by PCR-amplification, cloning and sequencing of the DNA portion (Lerner et al., EP0643778B1). In these DNA-encoded libraries, each compound in the library is attached to a unique identifier that “encodes” the chemical structure of the molecule to which it is attached. This way, the structure of a molecule that is selected in the screening assay can easily be decoded by the attached unique identifier. DNA-encoded libraries have also been generated by means of DNA-templating. In this approach, DNA templates direct the synthesis of the encoded compounds (Walder et al., Proc. Natl. Acad. Sci. USA (1979), 76, 51-55; Bruick et al., Chemistry and Biology (1996), 3: 49-56; Liu et al., WO02/074929A2; Pedersen et al., WO02/103008A2). Moreover, when these libraries are used in affinity selection experiments, the DNA of the recovered DNA-compound complexes can be amplified by PCR, and subsequently used in a new DNA-templated synthesis round, which directly amplifies the recovered compounds.