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.
Highlights
Fragment-based screening by NMR has evolved as a remarkable approach within the drug discovery process 25 years after the proposal of this approach (Shuker et al 1996)
Fragment-based drug discovery (FBDD) has been an important tool in identifying initial hits against difficult targets and thereby has become one of the foremost and popular methods to be used within the pharmaceutical and biotechnology industry (Baker 2013; Murray and Rees 2009)
In order to close-in this gap, we present here an integrated approach using commercially available state-of-the-art software Complete Molecular Confidence for quantification (CMC-q) and CMC-assist (CMC-a) developed by the company Bruker, 1H-NMR measurements and liquid chromatography-mass spectrometry (LC/MS) for characterization of the integrity and solubility of the fragments
Summary
Fragment-based screening by NMR has evolved as a remarkable approach within the drug discovery process 25 years after the proposal of this approach (Shuker et al 1996). The limited availability of high-quality chemical libraries for academia narrows the chances of discovering specific leads which can be developed into a drug candidate The former challenge has been overcome by initiating large consortiums involving several academic institutes which work like a “gear-box” and assembles the necessary manpower, materials and instrumentation and strive towards translational research. The average QED of this set of compounds is 0.68 showing a low weight given to the unwanted substructure alerts in the calculation This simple analysis of molecular clusters and QED underlines the fact that the iNEXT fragment library is relatively of high quality in its composition and can be used for FBS with a higher chance to identify drug like lead candidate. Storage of the fragment solutions in matrix tubes instead of deep-well plates is preferred
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