Are you looking for a fragment library that supplies the following data package for each aqueous soluble fragment? Provision of this data will enable practitioners to rapidly build fragment pools and initiate screening.
Key Organics is pleased to announce the release of the 2nd Generation BIONET Premium Fragment Library. The library has been constructed in collaboration with the Center for the Development of Therapeutics, Broad Institute and NMX Research and Solutions Inc.
1H NMR was employed to select compounds with appropriate solution behavior amenable to biophysical analysis in physiologically relevant aqueous solution. Each singleton sample consisted of nominal 300 μM compound in buffer (50 mM sodium phosphate pH 7.4, 100 mM NaCl). 1H NMR spectra were acquired on a 600 MHz spectrometer equipped with a helium cryoprobe that significantly increased signal-to-noise. Simple 1D 1H NMR spectra were acquired along with a series of 1D 1H CPMG spectra, which were used to detect compounds showing potential aggregation in aqueous solution. The CMC Assist automation software allowed for automatic readout of the fragment concentration that was experimentally derived from integrating the NMR resonances of each singleton sample and referencing to standardized samples using the ERETIC module (Bruker Spectrospin Inc.)4. The CMC Assist module also allowed for verification of each singleton spectrum to determine if the spectral attributes were consistent with the proposed primary structure of the corresponding fragment. This exercise was also complemented by an automated analysis using Spectral DB software (ACD Inc.).
The spin−spin relaxation Carr−Purcell−Meiboom−Gill NMR experiment has been employed to detect and remove aggregate species from Key Organics BIONET Premium Fragment library.5
Small molecules can self-assemble in aqueous solution into a wide range of nanoentity types and sizes each having their own unique properties. This has important consequences in the context of drug discovery including issues related to nonspecific binding, off-target effects, and false positives and negatives.
The spin−spin relaxation Carr−Purcell−Meiboom−Gill NMR experiment is sensitive to molecular tumbling rates and can expose larger aggregate species that have slower rotational correlations. The strategy easily distinguishes lone-tumbling molecules versus nanoentities of various sizes. The technique is highly sensitive to chemical exchange between single molecule and aggregate states and can therefore be used as a reporter when direct measurement of aggregates is not possible by NMR.
Key Organics in collaboration with Cayman Chemical have implemented an SPR Clean screen on the Fragment Library and the results are available for customers. An SPR Clean Screen aids identification of residual binding of fragments to the target molecule and/or the sensor surface. Fragment screening cycles do not normally include regeneration, and residual binding can affect subsequent cycles and mask weak binding of other fragments. An SPR Clean Screen is performed by injecting single concentrations of each fragment over reference and target surfaces.
All the fragments in the clean screen, with exception to those that showed irregular sensorgrams, were run at 1mM and showed the typical square-shaped sensorgram expected. Therefore, in the given experimental conditions, the fragments are soluble in ≥ 1mM in in PBS-P+.
# clusters at 0.85 Tanimoto similarity (MACCS 166-bit MOE) = 951. 951/1149 = 82.7%
No Data Found
1. Rules for identifying potentially reactive or promiscuous compounds. Bruns et al, J. Med. Chem, 2012 (53).
2. Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53 (7), 2719–2740.
3. Pearce, B. C.; Sofia, M. J.; Good, A. C.; Drexler, D. M.; Stock, D. A. J. Chem. Inf. Model. 2006, 46 (3), 1060–1068.
4. Akoka, S.; Barantin, L.; Trierweiler, M. Anal. Chem. 1999, 71, 2554-2557.
5. Yann Ayotte, Victoria M. Marando, Louis Vaillancourt, Patricia Bouchard, Gregory Heffron, Paul W. Coote, Sacha T. Larda, and Steven R. LaPlante, J. Med. Chem. 2019, 62, 7885−7896.
The BIONET Premium Fragment library is now available in milligram or micromolar quantities. Cherry picking is available.
For further information or to discuss your requirements, please contact Andrew Lowerson by email or on +44 (0)1840 212137
We maintain good stock levels of our Fragment Libraries. Indeed, a large proportion of our collection is available in gram quantities; this means we can ensure a very high level of re-supply of originally tested compounds.
If you want to explore SAR by catalogue or some initial Chemistry we can also assist with hit follow up (nearest neighbour/analogue searching) and Hit to Lead Chemistry.
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