Journal
REACTION CHEMISTRY & ENGINEERING
Volume 4, Issue 4, Pages 658-662Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8re00327k
Keywords
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Funding
- National Key Research and Development Program of China [2016YFB0301501]
- National Natural Science Foundation of China [21776130]
- Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture [XTD1821, XTD1802]
- Top Notch Academic Programs Project of Jiangsu Higher Education Institutions
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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 hampered by (i) the poor reactivity of potential inhibitors at low concentration; (ii) the reduction of protein activity or the decomposition 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 flowbased 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 accuracy of identification of potential inhibitors was improved. This system was validated by a case study that identified competitive inhibitors 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.
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