Microflow-based dynamic combinatorial chemistry: a microscale synthesis and screening platform for the rapid and accurate identification of bioactive molecules

摘要

Protein-directed dynamic combinatorial chemistry (DCC) has emerged as an efficient tool for the rapid identification of bioactive molecules in modern drug discovery. However, the applications of protein-directed DCC have been significantly ham- pered by (i) the poor reactivity of potential inhibitors at low con- centration; (ii) the reduction of protein activity or the decomposi- tion of potential inhibitors owing to long equilibration times; and (iii) limited analytical detection methods capable of processing large libraries. Here we report the development of a rapid flow- based synthesis and screening platform that integrates both microscale synthesis and identification of protein binders from protein-directed dynamic libraries into a single modular unit. By using microflow synthesis, the processes of compound synthesis and binding to the target protein were accelerated, and the accu- racy of identification of potential inhibitors was improved. This sys- tem was validated by a case study that identified competitive in- hibitors of bovine serum albumin (BSA). A significant reduction in equilibration time and an increased sensitivity for the identification of protein binders were acquired. Owing to the microscale effect, a new inhibitor for BSA, which was not found in batch mode, was discovered in the microflow system and the interaction of the new binder with BSA was also investigated.