Fragment-based drug discovery (FBDD) has become an established method for target-based drug design [1-3], offering an alternative to the high-throughput screening (HTS) approach. The primary advantage of using fragments – very small organic molecules – is their low complexity and associated higher binding probability . Other benefits of FBDD include smaller compound space (which offers increased combinatorial advantages), higher hit rates, and lower protein requirements . However, using fragments has its challenges – they usually bind weakly to their targets and, thus, demand highly sensitive methods for hit detection. Aiming to overcome this issue and efficiently identify the event of weak fragment binding to a specific target, FBDD applies various biochemical, biophysical, and computational techniques [1,2]:
- Nuclear magnetic resonance (NMR) methods (both ligand- and target-based), including
- 19F NMR spectroscopy
- saturation transfer difference spectroscopy (STD-NMR)
- gradient spectroscopy (waterLOGSY)
- 1H-15N heteronuclear single quantum coherence (HSQC), etc
- X-ray crystallography
- Surface plasmon resonance (SPR)
- Isothermal titration calorimetry (ITC)
- Microscale thermophoresis (MST)
- Thermal shift assays (TSAs)
- Weak affinity chromatography
- Filtering methods: ALARM NMR, PAINS, etc
In particular, 19F NMR spectroscopy [5-7] is widely used for fast and sensitive detection of fragment hits by employing the sharp and strong signal of fluorine in NMR spectra. The approach allows identifying various drug-like fluorine-substituted fragments, individually and in compound mixtures, or cocktails (Fig. 1). This simple, robust, and low-cost technique successfully contributes to all stages of the FBDD pipeline .
Fig. 1. 19F NMR spectrum of a sample pool of 10 fluorine-containing fragments selected for the Life Chemicals Fluorine Fragment Cocktails. All peaks are assigned to the corresponding compounds
X-ray crystallography generally supports the screening techniques and provides the structural models for identified fragments. However, this method itself appears to be a powerful tool for fragment screening [9,10] due to its high sensitivity, the unlikeliness of false positives, and direct hit validation through observing the 3D structure of protein-fragment complexes. Weak points of this experimental approach, such as technical difficulty, high cost, and relatively low throughput, can partially be overcome by recent technological improvements and are often outweighed by the advantageous output of the method.
To support the fragment-based drug discovery projects, we carefully select the fragment-like screening compounds and apply the advanced approaches to create our proprietary collection of Fragment Libraries. The fragment space offered by Life Chemicals (Fig. 2) comprises over 50,600 in-stock fragments in the General Fragment Library and over 230,000 virtual fragment-like molecules in the Collection of Tangible Fragments.
An early assessment of the solubility of fragments is crucial as it may limit their use in various screening techniques of FBDD in drug discovery projects. To address this issue, we developed our in-house high-throughput technique of kinetic and thermodynamic determination of aqueous solubility and prepared our featured Fragment Library with Experimental Solubility.
Meanwhile, the Covalent Fragment Library was specially designed to facilitate covalent fragment screening to provide highly selective irreversible inhibitors.
Please, contact us at email@example.com for any details and quotations.
Fig. 2. Predicted “fragment space” coverage of Life Chemicals fluorinated fragments (in red) is similar to the coverage of > 100k commercially available fluorinated fragments from the eMolecules (in blue).
Please, visit our Website for more information and download SD files with compound structures in the Downloads section. Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.
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- Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H. (2016). Twenty years on: the impact of fragments on drug discovery. Nature Reviews Drug Discovery, 15(9), 605–619. doi:10.1038/nrd.2016.109
- Kirsch, P., Hartman, A. M., Hirsch, A. K. H., & Empting, M. (2019). Concepts and Core Principles of Fragment-Based Drug Design. Molecules, 24(23), 4309. doi:10.3390/molecules24234309
- Hann, M. M., Leach, A. R., & Harper, G. (2001). Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery. Journal of Chemical Information and Computer Sciences, 41(3), 856–864. doi:10.1021/ci000403i
- Dalvit, C., Fagerness, P. E., Hadden, D. T. A., Sarver, R. W., & Stockman, B. J. (2003). Fluorine-NMR Experiments for High-Throughput Screening: Theoretical Aspects, Practical Considerations, and Range of Applicability. Journal of the American Chemical Society, 125(25), 7696–7703. doi:10.1021/ja034646d
- Kang C. B. (2019). 19F-NMR in target-based drug discovery. Curr Med Chem. 26, 4964. doi: 10.2174/0929867326666190610160534
- Lingel, A., Vulpetti, A., Reinsperger, T., Proudfoot, A., Denay, R., Frommlet, A., … Frank, A. (2020). Comprehensive and High‐Throughput Exploration of Chemical Space Using Broadband 19F NMR‐Based Screening. Angewandte Chemie International Edition. doi:10.1002/anie.202002463
- Norton, R., Leung, E., Chandrashekaran, I., & MacRaild, C. (2016). Applications of 19F-NMR in Fragment-Based Drug Discovery. Molecules, 21(7), 860. doi:10.3390/molecules21070860
- Patel, D., Bauman, J. D., & Arnold, E. (2014). Advantages of crystallographic fragment screening: Functional and mechanistic insights from a powerful platform for efficient drug discovery. Progress in Biophysics and Molecular Biology, 116(2-3), 92–100. doi:10.1016/j.pbiomolbio.2014.08.004
- Schiebel, J., Krimmer, S. G., Röwer, K., Knörlein, et al. (2016). High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits. Structure, 24(8), 1398–1409. doi:10.1016/j.str.2016.06.010