Rapid Generation of Hyperdiverse 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-weeks to < 1 hour while accessing quintillion-member libraries with diversities orders of magnitude beyond those achievable with current technologies. Flow synthesis is thus a powerful approach for the rapid generation of hyperdiverse libraries for selection-based drug discovery.