Cyclic Structures for DNA-Encoded Libraries

In the subsequently described project, the aim is to produce a series of DNA-encoded libraries consisting of cyclic structures. Initial work will focus on generation of a small library of macrocycles, whilst subsequent focus will be on small molecules produced via rhodium carbenoids. The libraries formed will be screened against protein targets available in the NICR drug discovery portfolio, and made available to collaborators.
With respect to the first library of macrocycles, initial work will involve the development of a synthetic scheme that will be compatible with DNA to form the macrocyclic structures. Figure 1 illustrates the typical structure of library members that will be developed. Investigations will be conducted in the absence of DNA tags whilst a suitable method is developed for the model system. It is likely that suggested conditions will need to be altered to ensure compatibility with DNA. Subsequently, these reactions shall be conducted on-DNA to result in the formation of a small chemically diverse library.

The choice of which compounds to include in the library will be aided in part by binding simulation software, such as MoE, to allow determination of which structures are best to explore initially. In addition, such software shall be used to investigate a series of macrocycles that contain four amide linkers, (and as such four points of diversity). Results of these simulations will be used to decide if exploration into these systems should also be conducted.
Both L- and D-amino acids will be explored to determine what effect this has on the properties of the library members. Additional modifications may also be investigated, such as N-methylation, as this has been reported to influence affinity and bioavailability of these structures.
Initial work for the second part of the project will involve development of a suitable synthetic scheme to yield a linear species such as that shown in figure 2. As for the work performed with macrocycles, synthesis will first be conducted in the absence of encoded tags to allow development of the methodology. Subsequently, library generation will be performed on-DNA, and resulting compounds will be screened.

For both approaches- macrocyclic structures and rhodium carbenoids- off-DNA work will focus on synthesis of a small number of test molecules; on-DNA techniques will first be explored using a fixed sequence of DNA, in order to create a small 4x4x4 library (64 molecules). Once a suitable synthetic route has been identified, encoded library synthesis will be used to create a larger 96 x 96 x 96 library.
Outcomes of the project involve both the discovery of new hit compounds that could potentially be developed into useful medicinal agents, aswell as the development of DNA-compatible chemistry for these systems. This latter feature would help increase the versatility of DNA-encoded libraries, and thus enhance them as a useful tool in drug discovery.