Fragment Screening & Lead Discovery Services
Fragment Screening & Lead Discovery Services
Hit identification, hit to lead & lead optimization services
SARomics Biostructures' fragment screening, structure-based lead discovery, and lead optimization services offer access to our proprietary weak-affinity chromatography (WAC™) screening technology. Our services include:
Our hit-to-lead & lead optimization services are guided by X-ray crystallographic analysis of the structure of the protein target in complex with the compounds of interest.
WAC™ is a robust and cost-efficient screening method. It can be combined with biophysical screening techniques for hit identification and verification, such as thermal-shift assay (DSF), isothermal titration calorimetry (ITC), and NMR spectroscopy. The commercial rights of the WAC™ screening technology are jointly owned by SARomics Biostructures and our in-house partner Red Lead Discovery.
Different drug discovery strategies can be applied depending on the availability of structural information. Our recent blog posts also discuss the subject of drug discovery strategy choice and the application of structural biology in drug discovery.
For details of the services, please follow the links below.
- Fragment screening & hit identification using WAC™ screening technology (proprietary fragment library or custom compound screening library)
- Structure-based hit to lead and lead optimization services
- Computational Chemistry services: pharmacophore and shape-based virtual screening services, scaffold hopping, design of screening library, QSAR analysis, and compound optimization
- Biochemical and cell-based assay and in vitro ADME
Our hit-to-lead & lead optimization services are guided by X-ray crystallographic analysis of the structure of the protein target in complex with the compounds of interest.
WAC™ is a robust and cost-efficient screening method. It can be combined with biophysical screening techniques for hit identification and verification, such as thermal-shift assay (DSF), isothermal titration calorimetry (ITC), and NMR spectroscopy. The commercial rights of the WAC™ screening technology are jointly owned by SARomics Biostructures and our in-house partner Red Lead Discovery.
Different drug discovery strategies can be applied depending on the availability of structural information. Our recent blog posts also discuss the subject of drug discovery strategy choice and the application of structural biology in drug discovery.
For details of the services, please follow the links below.
Weak-affinity chromatography
At the center of our fragment screening & lead discovery services is the high throughput (2000-3000 cmpds/week) proprietary weak-affinity chromatography (WAC™) screening technology, which provides high-quality data and has been validated against NMR spectroscopy and X-ray crystallography.
Proprietary fragment library
Our fragment library contains a collection of 1300 low-MW (<220) MedChem-friendly compounds (also available as neat samples, DMSO and DMSO-d6 solutions), designed to be general-purpose (not target-directed) covering diverse chemical space. Custom compound libraries can also be run.
Computational chemistry services
Computation chemistry is an integral part of structure-based lead discovery. Our team has gathered extensive experience in computational chemistry and may provide a wide range of services, including:
- Virtual screening services
- Pharmacophore and shape-based virtual screening
- Ligand-based drug design
- Scaffold hopping, etc.
Some answers to possible questions related to structure-based lead discovery strategies may be found in our Learning Center and may help you design your project. You may also contact us to present the details of our services and discuss your project.
WAC™ screening technology
WAC™ Facts
* Screening and binding assay in one experiment
* Measure fragment affinity to immobilized protein
* Built-in quality control (MS)
* Measure fragment affinity to immobilized protein
* Built-in quality control (MS)
Key Advantages
- Robust and accurate (validated against NMR and X-ray)
- Quick set-up and workflow (3 weeks turnaround)
- High throughput (>5000 cmpds/week)
- Low material consumption (<5 mg protein)
- Find mM hits by screening fragments at low concentrations (1-5 μM)
- Hit rates from 1% to 20%, (avg 6%)
Applications
* Screen for novel chemical starting points
* Assess the druggability of new targets
* Find differentiated backups in mature projects
* Rescue mode for challenging targets (PPI etc.)
* Assess the druggability of new targets
* Find differentiated backups in mature projects
* Rescue mode for challenging targets (PPI etc.)
Basics of WAC™ screening technology
WAC™ screening technology is the primary compound screening method used within our lead discovery services program. It is based on covalent immobilization of the protein target on a standard high-performance liquid chromatography (HPLC) column. A solution of small molecular weight fragments or larger compounds is injected into the column. During elution, the fragments with a higher affinity for the protein will stay on the column longer than those with a low 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 used for compound screening, e.g., X-ray crystallography, protein NMR spectroscopy, or isothermal titration calorimetry (ITC).
After the initial hit identification, NMR spectroscopy or X-ray crystallography can be used to gain additional insights into the details of the interactions of a compound with the protein. Ligand efficiency and ligand binding energy may also be estimated to guide the hit-to-lead and lead optimization processes.
The commercial rights of the WAC™ screening technology are jointly owned by SARomics Biostructures and our in-house partner Red Glead Discovery.
After the initial hit identification, NMR spectroscopy or X-ray crystallography can be used to gain additional insights into the details of the interactions of a compound with the protein. Ligand efficiency and ligand binding energy may also be estimated to guide the hit-to-lead and lead optimization processes.
The commercial rights of the WAC™ screening technology are jointly owned by SARomics Biostructures and our in-house partner Red Glead Discovery.
Proprietary fragment library
Our fragment library includes a collection of 1300 compounds (available as neat samples, 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.)
More than 90% commercially available, facilitating rapid SAR-generation
On the image: Klara Jonasson, PhD,
Senior Research Scientist, Red Glead Discovery
Computational chemistry & virtual screening services
Computational chemistry methods can be efficiently used in lead discovery, and they are essential in virtual screening and structure-based lead design. The process provides a combination of pharmacophore and shape-based virtual screening of fragments or large compound libraries, ligand docking, scaffold hopping, QSAR analysis, and ligand optimization, allowing substantial acceleration of the lead discovery process. Our virtual library used for in silico compound screening contains millions of purchasable molecules. It has already been pre-filtered to remove, e.g., reactive groups and compounds that are too lipophilic.
Our computational chemistry team collaborates closely with other teams to efficiently drive the project from hit identification, hit to lead, lead optimization, and candidate drug nomination. Our learning center discusses the details of various lead design strategies, which can be followed depending on the type of information at hand.
Our computational chemistry team collaborates closely with other teams to efficiently drive the project from hit identification, hit to lead, lead optimization, and candidate drug nomination. Our learning center discusses the details of various lead design strategies, which can be followed depending on the type of information at hand.
Our computational chemistry and virtual screening services include (but are not limited to) the following options:
- Pharmacophore and shape-based fragment screening
- Ligand-based drug design
- Scaffold hopping
- Design of screening library
- QSAR analysis and optimization
As part of our computational chemistry services, we also offer in silico protein optimization and structure-based design of biological drugs (biologics) and peptides using quantitative structure-activity relationships (QSAR) methodology as implemented in our proprietary ProPHECY™ software package.
On the image: Bo Svensson, PhD, Director, in silico discovery
Our publications are our best testimonials!
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
For a full list please visit our publications list.
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
For a full list please visit our publications list.
For related services please follow the respective link
Gene-to-structure services
Protein NMR spectroscopy
Antibody structure
Structure-based design of biological drugs