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Lead Discovery and Optimization

The screening and deconvolution of Torrey Pines Institute' libraries leads to the rapid identification of lead individual compounds as well as information on structural analogs. Inherent in the deconvolution of the Torrey Pines Institute libraries is a certain amount of structure activity relationship ("SAR") data. This information alone or in conjunction with prior knowledge of the target(s) and/or additional leads is used to optimize the current leads.

Structure of DNA methyltransferase. This enzyme catalyzes the transfer of a methyl group to DNA and it is a very promising target to explore new anticancer drugs.Structure of DNA methyltransferase. This enzyme catalyzes the transfer of a methyl group to DNA and it is a very promising target to explore new anticancer drugs.

Target Based

When specific information is known about the target from crystallography or NMR studies, three dimensional models can be used to optimize leads. For example, leads derived from our libraries and other compound collections can be "docked" into the model targets to both identify putative binding modes as well as identify opportunities for increasing activity. As an example, in previous studies using docking models obtained with small molecules and protein kinases specific modifications to leads were identified. These structural modifications were designed to improve activity by including nitrogen atoms at specific positions in order to make hydrogen bonds with the target.

Another use of docking approaches is the virtual or in silico screening of synthetic combinatorial libraries and other compound collections. Using this approach we have identified novel protein kinase B and DNA metiltransferase inhibitors as potential therapeutic agents for the treatment of cancer. The outcome of such calculation is to predict what molecules within a library or collection are most and least likely to be active with a given receptor. Docking different combinatorial libraries that differ in the core scaffold with the same target enables the prediction of what library is the most likely to have activity. This process can be seen as a docking-based scaffold ranking and can be used to complement our traditional approach.

Ligand Based

Whether the leads and structural analogs are derived solely from the screening of Torrey Pines Institute' libraries or additional information is known from others sources, the information can be used to identify and optimize the leads from a ligand perspective. For example, active leads can be overlayed on top of each other to identify key common features (Figure below). This information can be used to aid in scaffold hopping and in in silico screening of other TPMIS libraries as well as other compound collections.Bioorg. Med. Chem, 17:5583, 2009 Bioorg. Med. Chem.16:5932, 2008Bioorg. Med. Chem, 17:5583, 2009 Bioorg. Med. Chem.16:5932, 2008

Additionally novel computational strategies are in constant development to speed up in silico screening of compound libraries. Figure below shows how after applying a dynamic clustering protocol a reduced number of conformers is obtained while maintaining a biologically relevant ensemble.

Individual Compounds Synthesis

Torrey Pines Institute possesses the capability to rapidly synthesize, purify and characterize (by LCMS and NMR) any individual compound contained in the libraries as well as structural analogs in quantities needed for any secondary lead confirmation assays. This capability is due to the fact that the synthetic schemes have already been developed and optimized when the library was developed. Thus, this ability facilitates the opportunity to execute necessary experiments before entering clinical trials.

Schematic representation of the reduction of conformers after applying a dynamic clustering protocolSchematic representation of the reduction of conformers after applying a dynamic clustering protocol