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.

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:

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:

Customers are supplied with the following data package for each fragment purchased:

The parameters used in the design of the Fluorine Fragment Library:

The library excludes substructures identified as promiscuous or reactive by the following empirically determined rejection rules:

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

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 fragments@keyorganics.net

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:

The parameters used in the design of the library are:

Properties were calculated using DataWarrior1 and FAFDrugs42.

The library excludes substructures identified as promiscuous or reactive by the following empirically determined rejection rules:

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

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.

Acrylamide and Chloroacetamide 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

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:

Fragment integrity & formats:

Database Download

To download all the latest BIONET Fragment databases.

Also to receive our updates please register here.

POA Enquiry Form

We aim to give you a response from a qualified scientist within a hour

Enquire about pack size

Please specify your custom pack size below