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Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries

[Image: see text] 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 li...

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Detalles Bibliográficos
Autores principales: Mata, J. Miguel, van der Nol, Edith, Pomplun, Sebastian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472510/
https://www.ncbi.nlm.nih.gov/pubmed/37556835
http://dx.doi.org/10.1021/jacs.3c04899
Descripción
Sumario:[Image: see text] 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.