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NMR quality control of fragment libraries for screening

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Item Type:Article
Title:NMR quality control of fragment libraries for screening
Creators Name:Sreeramulu, S. and Richter, C. and Kuehn, T. and Azzaoui, K. and Blommers, M.J.J. and Del Conte, R. and Fragai, M. and Trieloff, N. and Schmieder, P. and Nazaré, M. and Specker, E. and Ivanov, V. and Oschkinat, H. and Banci, L. and Schwalbe, H.
Abstract:Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of "poised fragments" with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process.
Keywords:Drug Discovery, FBDD, Ligands, Fragment, Quality Control, Solubility, NMR
Source:Journal of Biomolecular NMR
Page Range:555-563
Date:November 2020
Official Publication:https://doi.org/10.1007/s10858-020-00327-9
PubMed:View item in PubMed

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