DNA-encoded Chemistry Technology (DEC-Tec) for Effective Drug-discovery Screening
The NMR and Drug Metabolism Core works closely with the Baylor Center for Drug Discovery, which provides access to compound libraries and DEC-Tec libraries. Pharmaceutical companies have traditionally assembled extremely expensive million-component drug libraries for high-throughput screening (HTS) directed toward possible drug targets. Despite the expense of this enormous undertaking, these compound collections are often unsuccessful in generating active compounds to some drug targets because they are not composed of diverse molecular types.
A more economical approach that enables the generation of greater small-molecule diversity is the preparation of DNA-encoded libraries. DEC-Tec, conceived as a small-molecule analogy to high-affinity biopolymer ligand discovery approaches such as phage display and aptamer selection, allows for the efficient interrogation of extremely large and diverse compound sets (collections up to 100 billion have been described) as a single mixture. The DEC-Tec library of drug-like molecules, each of which is attached to a unique DNA sequence that acts as a “bar code” defining its synthesis, can be incubated in a single tube with a target protein and subjected to washes to isolate the most tightly binding species and to identify the chemical features of these binders by deep sequencing. No assay or structural knowledge of the target protein is required as compounds within the library are selected by affinity. This DEC-Tec strategy permits the identification of the small-molecule “needle” in a billion-compound “haystack”. Compared to typical high-throughput screening (HTS), DEC-Tec requires a relatively small investment to establish, and requires only micrograms of target protein: an amount within the capability of even the smallest academic laboratory.
Additionally, the billion-compound collections generated by DEC-Tec represent 1000 times more compounds than the most state-of-the-art HTS facility can screen. This expanded number of small-molecules provides enhanced opportunities for hit discovery against a range of disease targets. There are several published examples of the utility of DEC-Tec in discovering effective small-molecule ligands. The DEC-Tec platform has the capacity to drastically improve the success rate of discovery and subsequent development of small-molecule probes and lead compounds within the academic community.