Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries
peer-reviewed · Journal of the American Chemical Society · 2023
| Date | 2023-08-30 |
| Type | peer-reviewed |
| Venue | Journal of the American Chemical Society |
| Publisher | American Chemical Society (ACS) |
| Contribution | review |
| DOI | 10.1021/jacs.3c04899 |
| Citations (OpenAlex) | 26 |
Abstract
Discovering new bioactive molecules is crucial for drug development. Finding a hit compound for a new drug target usually requires screening of millions of molecules. Affinity selection based technologies have revolutionized early hit discovery by enabling the rapid screening of libraries with millions or billions of compounds in short timeframes. In this Perspective, we describe recent technology breakthroughs that enable the screening of ultralarge synthetic peptidomimetic libraries with a barcode-free tandem mass spectrometry decoding strategy. A combination of combinatorial synthesis, affinity selection, automated de novo peptide sequencing algorithms, and advances in mass spectrometry instrumentation now enables hit discovery from synthetic libraries with over 100 million members. We provide a perspective on this powerful technology and showcase success stories featuring the discovery of high affinity binders for a number of drug targets including proteins, nucleic acids, and specific cell types. Further, we show the usage of the technology to discover synthetic peptidomimetics with specific functions and reactivity. We predict that affinity selection coupled with tandem mass spectrometry and automated de novo decoding will rapidly evolve further and become a broadly used drug discovery technology.
Methods and tools
- MS-encoded library hit discovery perspective: A perspective on affinity selection from ultralarge synthetic peptidomimetic libraries decoded by automated de novo MS/MS sequencing rather than barcodes.