Rapid generation of hypervariable chemical libraries

Flow chemistry has revolutionized polyamide synthesis, allowing access to entire synthetic proteins in a matter of hours. In principle, the efficiency of similar flow-based methods should also allow rapid access to extremely large compound libraries for selection-based drug discovery. To determine whether flow chemistry could be used for polyamide library synthesis, we adapted a semi-automated flow platform to the task of making combinatorial libraries, including both canonical and noncanonical amino acid building blocks. Using this platform, we then demonstrate the ability to decrease the turnaround time for custom library synthesis from days to <1 h while accessing quintillion-member libraries with orders of magnitude more compounds than can be made with current technologies. Flow synthesis is thus a powerful approach for the rapid generation of hypervariable libraries for selection-based drug discovery.