2. Academic Validation
  3. NMR quality control of fragment libraries for screening

NMR quality control of fragment libraries for screening

  • J Biomol NMR. 2020 Nov;74(10-11):555-563. doi: 10.1007/s10858-020-00327-9.
Sridhar Sreeramulu 1,  Christian Richter 1,  Till Kuehn 2,  Kamal Azzaoui 3,  Marcel Jules José Blommers 3,  Rebecca Del Conte 4,  Marco Fragai 4,  Nils Trieloff 5,  Peter Schmieder 5,  Marc Nazaré 5,  Edgar Specker 5,  Vladimir Ivanov 6,  Hartmut Oschkinat 5,  Lucia Banci 4,  Harald Schwalbe 7 8 9
Affiliations

Affiliations

  • 1 Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical Biology, Goethe University, Frankfurt, Germany.
  • 2 Bruker, Fällanden, Switzerland.
  • 3 Saverna Therapeutics, Biel-Benken, Switzerland.
  • 4 Magnetic Resonance Center and Department of Chemistry, University of Florence, Florence, Italy.
  • 5 Department of NMR-Supported Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
  • 6 Enamine, ENAMINE Ltd., 78 Chervonotkatska Street, Kiev, 02660, Ukraine.
  • 7 Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical Biology, Goethe University, Frankfurt, Germany. Schwalbe@nmr.uni-frankfurt.de.
  • 8 German Cancer Consortium (DKTK), Heidelberg, Germany. Schwalbe@nmr.uni-frankfurt.de.
  • 9 German Cancer Research Center (DKFZ), Heidelberg, Germany. Schwalbe@nmr.uni-frankfurt.de.
PMID: 32533387 DOI: 10.1007/s10858-020-00327-9
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; Fragment; Ligands; NMR; Quality control; Solubility.

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