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BIONET Fragment Libraries
2nd generation BIONET Premium Fragment Library
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.
- Aqueous buffer 1H NMR pdf
- Aqueous buffer 1H NMR raw data file
- 1H NMR chemical shifts supplied in an excel file
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.
Key Features & Benefits:
- 1166 compounds with experimentally assured aqueous solubility in PBS buffer.
- Excludes fragments deemed to aggregate as determined by 1H NMR spectra
- 1H NMR pdf and raw data files provided for all compounds purchased, chemical shifts provided for all compounds in an excel file.
- Strictly meet Astex Rule of 3 including polar surface area ≤ 60 and number of atoms ≤ 16
- Includes 445 fragments found in approved drugs and >1100 sharing cores found in drugs
- Filtered to exclude promiscuous and reactive substructures
The BIONET Premium Fragment library is now available in milligram or micromolar quantities. Cherry picking is available.
BIONET 2nd Gen Premium Fragment Library Pack
A comprehensive review of the design process employed in constructing the 2nd Generation BIONET Premium Fragment Library is available as a PDF by clicking here
For further information or to discuss your requirements, please contact Andrew Lowerson by email or on +44 (0)1840 212137
BIONET Fluorine Fragment Library
Key Organics have expanded the BIONET Fluorine Fragment Library which now includes 533 fluorinated fragments. The library has the following key features and benefits:
Key Features & Benefits:
- Measured solubility in PBS buffer ≥ 100μM by ¹H NMR
- Fragments soluble in DMSO at 100mM
- Purity ≥ 95%
- Filtered for PAINS substructures
- Excludes fragments likely to form aggregates
Customers are supplied with the following data package for each fragment purchased:
- Aqueous buffer ¹⁹F NMR raw data file
- Aqueous buffer ¹H NMR raw data file
- ¹⁹F NMR chemical shifts
- Structures and Physiochemical properties in an sd file
The parameters used in the design of the Fluorine Fragment Library:
- Heavy atoms ≤21
- cLogP ≤ 3
- Hydrogen bond donors ≤2
- Hydrogen bond acceptors ≤4
- tPSA ≤ 72
- Rotatable bonds ≤ 3
The library excludes substructures identified as promiscuous or reactive by the following empirically determined rejection rules:
- Lilly MedChem Rules³
- PAINS⁴
- FAFDrugs4²
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.
¹⁹F and ¹H NMR curation for fragment prioritisation and library characterization
19F and 1H NMR were employed to select compounds with appropriate solution behaviour to be 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 19F and 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.)10. 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.).
Key Organics Fluorine Fragment Library excludes fragments likely to form aggregates.
The spin−spin relaxation Carr−Purcell− Meiboom−Gill NMR experiment has been employed to detect and remove aggregate species from Key Organics BIONET Premium and Fluorine Fragment libraries5.
Small molecules can self-assemble in aqueous solution into a wide range of nanoentity types and sizes (dimers, n-mers, micelles, colloids, etc.), 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.
Overview of calculated properties of the final library
Diversity Statistics:
# clusters at 0.85 similarity = 456 singletons. 490 clusters / 533 fragments = 91.9%
Diversity
No Data Found
References
1. DataWarrior: An Open-Source Program for Chemistry Aware Data Visualization and Analysis. J Chem Inf Model 2015.
2. FAFDrugs4: M.; Miteva, S.; Violas, M.; Montes, D.; Gomez, P.; Tuffery, B.; Villoutreix. Nucleic Acids Research. 2006,34 (2), W738–W744.
3. Rules for identifying potentially reactive or promiscuous compounds. Bruns et al, J. Med. Chem, 2012 (53).
4. Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53 (7), 2719–2740.
The BIONET Fluorine Fragment Library is available custom-weighed in milligram or micromolar quantities. Customers can purchase the entire library or select any number of compounds as required.
A comprehensive review of the design process employed in constructing the BIONET Fluorine Fragment Library is available as a PDF by clicking here
For further information or to discuss your requirements, please contact Andrew Lowerson by email or on +44 (0)1840 212137
BIONET Boronic acid fragments
Boronic Acids as Covalent Fragments
Fragments usually have low affinities for their targets and require sensitive biophysical methods such as NMR to detect binding. What if you could increase the affinity of fragments themselves?
Affinity can be increased by introducing a covalent bond between the fragment and the protein: Boronic acids can form reversible covalent bonds with the side chains of serines or threonines in proteins, with a preference for the highly reactive active-site residues found in hydrolytic enzymes.
Multiple researchers have assembled libraries of fragments containing reversible covalent “warheads”. The latest example by Marion Lanier, Mark Hixon, and collaborators at Takeda, featuring boronic acids appears in J. Med. Chem. 2017, 60, 5209-5215.
BIONET Boronic Acids from Key Organics
Key Organics have over 500 in-stock boronic acids available in small mg amounts for Fragment/HTS screening – you can download SDF’s of our fragment libraries at www.keyorganics.net or email [email protected]
Examples of BIONET Boronic Acid Fragments available from Key Organics:
BIONET bromine fragment library
Key Organics have constructed a BIONET Bromine Fragment Library which includes 314 brominated fragments.
Key Features & Benefits:
- Measured solubility in PBS buffer ≥ 100μM by ¹H NMR
- Fragments soluble in DMSO at 200mM
- Purity ≥ 95%
- Filtered for PAINS substructures
- Excludes fragments likely to form aggregates
The parameters used in the design of the library are:
- Heavy atoms ≤ 16
- MW ≤ 300
- clogP ≤3.3
- Hydrogen bond donors ≤3
- Hydrogen bond acceptors ≤4
- tPSA ≤ 70
- Rotatable bonds ≤ 3
Properties were calculated using DataWarrior1 and FAFDrugs42.
The library excludes substructures identified as promiscuous or reactive by the following empirically determined rejection rules:
- Lilly MedChem Rules³
- PAINS⁴
- FAFDrugs4²
¹H NMR curation for fragment prioritisation and library characterization
1H NMR were employed to select compounds with the appropriate solution behaviour to be amenable to rigorous 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 an 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.)10. 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.).
Key Organics Bromine Fragment Library exclude fragments likely to form aggregates
The spin−spin relaxation Carr−Purcell−Meiboom−Gill NMR experiment has been employed to detect and remove aggregate species from Key Organics BIONET Bromine 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.
Overview of calculated properties of the final library
Diversity Statistics
# clusters at 0.85 similarity = 205 singletons. 248 clusters / 314 fragments = 79%
Diversity
No Data Found
References
1. DataWarrior: An Open-Source Program for Chemistry Aware Data Visualization and Analysis. J Chem Inf Model 2015.
2. FAFDrugs4: M.; Miteva, S.; Violas, M.; Montes, D.; Gomez, P.; Tuffery, B.; Villoutreix. Nucleic Acids Research. 2006, 34 (2), W738–W744.
3. Rules for identifying potentially reactive or promiscuous compounds. Bruns et al, J. Med. Chem, 2012 (53).
4. Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53 (7), 2719–2740.
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.
BIONET Covalent Fragments
Drugs that covalently bond to their biological targets have a long history in drug discovery. There is an increased interest in covalent therapeutics in the literature and recent years have witnessed a significant increase in the number of drug candidates with covalent mechanism of action progressing through clinical trials or being approved; moreover, about 30% of marketed drugs are covalent binders. Screening fragments has its challenges, principally, the requirement for sensitive biophysical assays due to the low affinity of typical fragment hits. Fragments that can form a covalent bond with their target protein can overcome this challenge due to the increased affinity between the fragment and the target.
Key Organics has assembled a collection of covalent fragments containing cysteine-reactive electrophiles such as chloroacetamides and acrylamides.
Examples of Key Organics Chloroacetamide fragments
Examples of Key Organics Acrylamide fragments
Other chemical classes are available including Epoxides; Terminal alkynes; Nitro alkyls; Isothiocyanates; 2-Chloropyridines; Michael acceptors; Aldehydes; Boronic acids; Alkyl Halides and Activated nitriles.
Stock Quantities and re-supply for follow up research.
Typically, about 95% of the compounds in our collection are available in >20mg stock quantities and over 93% of the compounds are available in >100mg stock quantities. 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.
Advantages of purchasing directly from BIONET:
- Ease of purchasing directly through our online shop, by phone, or via e-mail
- Usually dispatched within 1 working day, from stock
- Dedicated customer relations department, real-time response
Fragment integrity & formats:
- Minimum Purity of fragments is >90% by LC-MS and/or 1H NMR with the majority being > 95%. Analytical data for every compound purchased can be provided on request.
- Fragment compounds are available in milligram or micromole amounts in powder form plated to your requirements. Bulk amounts available on request
Database Download
To download all the latest BIONET Fragment databases.
Also to receive our updates please register here.