Integrated Drug Discovery: WAC™ Fragment Screening and Lead Generation
The integrated drug discovery and structure-based drug design (SBDD) platform at SARomics Biostructures offers fragment screening and hit identification services using our proprietary weak-affinity chromatography (WAC™) screening technology. In addition, in collaboration with our in-house partner Red Glead Discovery, we provide full-range discovery services including hit expansion and hit-to-lead optimization, medicinal chemistry, computational chemistry and in silico drug design, X-ray crystallography and protein NMR, biophysical validation, biochemical and cell-based screening, in vitro ADME etc.
For a description of the full range of applications of the method, see below. For details of the technology you can also consult WAC™ basics.
WAC™ Screening Technology
WAC™ Facts
- Screening and binding assay in one experiment
- Measure fragment affinity to immobilized protein
- Built-in quality control (MS)
WAC™ Key Advantages
- Robust and accurate (validated against NMR and X-ray)
- Quick set-up and workflow (3 weeks turnaround)
- High throughput (2000-3000 cmpds/week)
- Low material consumption (<5 mg protein)
- Find mM hits by screening fragments at low concentration (1-5 μM)
- Output – High quality data for MedChem (hits with KD values)
WAC™ Applications
- Screen for novel chemical starting points
- Assess druggability of new targets
- Find differentiated backups in mature projects • Rescue mode for challenging targets (PPI etc.)
Proprietary fragment library
Our library includes a collection of 1300 fragments (available as neat sample, DMSO and DMSO-d6 solutions).
• 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)
• >90% commercially available facilitating rapid SAR-generation
Our services also include:
- Biophysical screening - Efficient hit identification using thermal-shift assay (DSF), isothermal titration calorimetry (ITC), NMR spectroscopy and X-ray crystallography.
- Computational chemistry & in silico drug design - Library design, hit expansion, pharmacophore- and shape-based virtual screening, scaffold hopping, QSAR analysis and optimization.
- Structural biology - Highly efficient structural biology platform with proprietary high-throughput crystallization and structure determination protocols.
- Medicinal chemistry - Through our collaboration with our inhouse partner Red Glead Discovery we offer expertise in lead optimization, biological characterization, medicinal chemistry and ADME.
Basics of the WAC™ screening technology
The WAC™ method is based on covalent immobilisation of the protein to be screened on a standard high-performance liquid chromatography (HPLC) column. A solution of small molecular weight fragments or larger compounds is injected into this column. During elution, the fragments that have higher affinity for the protein will stay on the column longer than those with low or no affinity. The fragments can be conveniently detected using mass- or UV spectrometry. This method is an efficient and lower-cost choice, compared to other biophysical screening methods that study ligand binding, e.g., X-ray crystallography, protein NMR spectroscopy or isothermal titration calorimetry (ITC).
After the initial hit identification, protein NMR or X-ray crystallography can be used to gain additional insights into the details of the interactions of the compound with the protein. Ligand efficiency and ligand binding energy may also be calculated.
Computational Chemistry & in silico Drug Discovery Services
Computational chemistry methods provide means for the combination of pharmacophore and shape-based screening of compound libraries, ligand docking, scaffold hopping, QSAR analysis and ligand optimization, allowing substantial acceleration of the drug discovery process. Our virtual library used in in silico screening contains millions of purchasable compounds. It has already been pre-filtered to remove e.g. reactive groups and compounds that are too lipophilic.
A more detailed outline of various drug discovery strategies, which can be designed depending on the type of information at hands, is discussed in our drug discovery technology pages.
Our computational chemistry and in silico drug discovery services include (but are not limited to) the following options:
- Pharmacophore and shape-based virtual screening
- Ligand-based drug design
- Scaffold hopping
- Design of screening library
- QSAR analysis and optimization
Recent publications that include contributions from SARomics Biostructures:
Korkmaz B, Lesner A, Wysocka M, Gieldon A, Håkansson M, Gauthier F, Logan DT, Jenne DE, Lauritzen C, Pedersen J (2019).
Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.
Biochem Pharmacol. 164, 349-367. https://doi.org/10.1016/j.bcp.2019.04.006
Gustafsson NMS, Färnegårdh K, Bonagas N, Ninou AH, Groth P, Wiita E, Jönsson M, Hallberg K, Lehto J, Pennisi R, Martinsson J, Norström C, Hollers J, Schultz J, Andersson M, Markova N, Marttila P, Kim B, Norin M, Olin T, Helleday T (2018).
Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination.
Nat Commun. 9, 3872. DOI: 10.1038/s41467-018-06287-x
Pippione AC, Federico A, Ducime A, Sainas S, Boschi D, Barge A, Lupino L, Piccinini M, Kubbutat M, Contreras J-M, Morice C, Al-Karadaghi S and Lolli ML. (2017). 4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade. Med. Chem. Commun. 8, 1850–1855. DOI: 10.1039/c7md00278e
To view a full list please visit our publications page.