Fragment Screening and Fragment-Based Drug Discovery Services
SARomics Biostructures provides drug discovery CRO services, including fragment screening and fragment-based drug design, with exclusive access to our leading NMR and crystallographic fragment screening and proprietary fragment libraries.
WAC™ fragment library screening
Together with RG Discovery, we provide fragment screening services using our proprietary weak-affinity chromatography (WAC™) technology. After seven years of rigorous testing, WAC™ has clearly demonstrated its cost-effectiveness as a high-throughput method for generating exceptional starting points for hit-to-lead Medicinal Chemistry programs, thereby advancing projects. For more details on the process, please refer to our blog post or download the information flyer below.
Biophysical Fragment Screening Services For Drug Discovery
Our comprehensive CRO platform for fragment screening services provides exclusive access to a proprietary fragment library and biophysical screening capabilities that include the following screening techniques:
- Weak affinity chromatography (WAC™)
- NMR spectroscopic screening
- Crystallographic fragment screening
- Computational chemistry & virtual screening
- In collaboration with Vipergen, we also offer screening using Vipergen’s unique DNA-encoded library (DEL) screening technologies.
Our fragment screening group collaborates closely with the medicinal chemistry team at RG Discovery to deliver a comprehensive, well-integrated fragment-based drug discovery and design (FBDD) process. We focus on driving the project from initial hit identification through hit expansion, lead generation, and optimization. Ultimately, our goal is to nominate the most promising candidate drug for further trials. Please visit our Knowledge Center for a discussion of the different structure-based drug design strategies. We also invite you to have a look at our blog post on the advantages of outsourcing early drug discovery projects.
NMR spectroscopy & Crystallographic Fragment Screening
NMR spectroscopy and protein crystallography are two powerful techniques for screening fragments in fragment-based drug discovery and design. They enable the identification of weak binders to proteins, revealing a detailed map of molecular interactions within the fragment-protein complex. Fragment screening uses a small library of molecular fragments with molecular weights in the 100-300 Da range. Additionally, the three-dimensional structure guides the expansion from hits to leads and the optimization of compounds’ affinities and specificities.
Our biophysical fragment screening services utilize a proprietary library of MedChem-friendly low-molecular-weight compounds (around 1300) for WAC and NMR screening. Additionally, we have a kinase-focused fragment library designed explicitly for crystallographic fragment screening (download the poster for details). These compounds are designed to cover diverse chemical spaces and are general-purpose. Customers can also use their own libraries for screening. Some characteristics of the library are listed below:
- Designed to be general-purpose (not target-directed), covering diverse chemical space.
- A focus on low-molecular-weight fragments (<220)
- Solubility data (DMSO, water) are available for >80% of the fragments
- Analytical data (LCMS, 1H-NMR) available for all fragments
- Designed to be MedChem friendly (HBDs, HBAs, and ring count, ClogP, functional groups, etc.)
- More than 90% commercially available, facilitating rapid SAR generation
See also our blog post on choosing a compound library for screening.
Our leading NMR fragment and larger ligand screening services are often run within our integrated drug discovery services projects. We regularly run compound validation, either in combination with our proprietary weak-affinity chromatography (WAC™) or other biophysical screening methods. Depending on the target protein, we can run either 1D ligand-detection experiments or use 2D spectra.
For 1D ligand detection, we can conduct either 1H or 19F experiments. We can identify potential binding sites by competition experiments with a known binder. In 2D experiments, the protein must generally be labeled with 15N (or 2H for large proteins). However, recent advances in NMR technology enable us to conduct NMR fragment screening on non-isotopically labeled samples by examining the methyl region of the 13C NMR spectrum. If the assignment is available, we can readily identify the binding epitope of various fragments at atomic resolution.
Practical implementation of crystallographic fragment screening became possible only with technical advancements, such as high-brilliance X-ray beams and automation at synchrotrons. The BioMax beamline at the MAX IV Laboratory has established a comprehensive crystallographic screening platform, FragMAX. It offers state-of-the-art instrumentation and a high-brilliance X-ray beam at the MAX IV synchrotron radiation facility.
At SARomics Biostructures, we provide crystallographic fragment screening CRO services, which make use of our proprietary library specifically designed for this type of experiment. Screening can be offered as a standalone service or as part of our fragment-based drug discovery program. Our dedicated team will support you at every stage of the project, including:
– Crystal preparation and optimization for soaking
– Determination of solvent tolerance of the crystals (fragments are dissolved in DMSO)
– Soaking of crystals (more than 400 data sets per day may need to be collected)
– Crystal mounting and high-throughput data collection
– Data processing and analysis
Our clients do not need to apply for synchrotron beamtime, since all experiments are conducted under our standard agreement with MAX IV.
Please view our blog post for more details about the crystallographic fragment screening technique.
- Pharmacophore and shape-based compound screening
- Ligand-based drug design
- Scaffold hopping
- Design of screening fragment library
- QSAR analysis and optimization
Computational Chemistry & Virtual Screening Services
Computational chemistry and virtual screening (in silico fragment screening) are crucial to fragment-based drug design. In addition to virtual screening, computational chemistry methods are often used during hit optimization and structure-based design of new lead molecules. We can also assess ligand efficiency through docking and employ a combination of pharmacophore- and shape-based virtual screening to optimize new ligands. Other methods, such as scaffold hopping and quantitative structure-activity relationships (QSAR) analysis, can also be used to identify new potential binders. These tools significantly speed up the drug discovery process. When screening compounds in silico, we utilize a virtual library containing millions of purchasable compounds that have already been filtered to remove reactive groups and excessively lipophilic molecules.
Our computational chemistry team closely collaborates with the medicinal chemistry, X-ray crystallography, and NMR spectroscopy teams throughout our fragment-based drug design process. This collaboration effectively advances the project from hit identification to structure-based hit expansion, structure-based hit-to-lead optimization, lead generation, and candidate drug nomination. Our Knowledge Center offers comprehensive information on various structure-based design strategies, informed by available data.
Recent publication: Discovery of selective galacten-1 inhibitors
Zetterberg FR, Diehl C, Håkansson M, Kahl-Knutson B, Leffler H, Nilsson UJ, Peterson K, Roper JA & Slack RJ (2023).
Discovery of Selective and Orally Available Galectin-1 Inhibitors
J. Med. Chem. 2023, 66, 24, 16980–16990
PDB entries:
8OJP – Human galectin 1 in complex with inhibitor (on hold until publication)
A new series of orally available α-d-galactopyranosides with high affinity and specificity for galectin-1 has been discovered. Researchers replaced six-membered aryl-triazolyl substituents in previously reported galectin-3-selective α-d-thiogalactosides with five-membered heterocycles such as thiazoles to achieve high affinity and specificity. One specific compound, GB1490, showed promising results (Kd galectin-1/3: 0.4/2.7 μM) and was further analyzed for selectivity across various galectins, demonstrating 6- to 320-fold selectivity, depending on the specific galectin class. The X-ray structure of GB1490 bound to galectin-1 revealed that the compound binds in a single conformation in the carbohydrate-binding site.
We invite you to visit our publications page to explore more examples of our contributions to projects.