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 platform offers access to our proprietary weak-affinity chromatography (WAC™) screening technology. Our services include:

  • 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. I
f required, 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.

Depending on the availability of structural information, different
drug discovery strategies can be applied. 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 (WAC™)

WAC fragment screening services
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

Proprietary fragment library screening, MedChem friendly compounds
Our fragment library contains a collection of 1300 low-mw (<220) MedChem friendly compounds (also available as neat sample, 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

Computational chemistry services by SARomics Biostructures
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 in the design of your project. Or just contact us for a presentation of the details of our services and for a discussion of 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)

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 concentration (1-5 μM)
  • Hit rates from 1% to 20%, (avg 6%)

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.)

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 immobilisation 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 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 used for compound screening, e.g., X-ray crystallography, protein NMR spectroscopy or isothermal titration calorimetry (ITC).

After the initial hit identification,
NMR spectroscopy (sometimes called BioNMR) 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 process.

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 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)

  • More than 90% commercially available facilitating rapid SAR-generation

Klara Jonasson, Red Glead Discovery

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 method provides means for the combination of pharmacophore and shape-based virtual screening of fragments or larger compound libraries, ligand docking, scaffold hopping, QSAR analysis and ligand optimization, allowing substantial acceleration of the lead discovery process. Our virtual library used in 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 and lead optimization and candidate drug nomination. Our learning center provides a discussion of the details of various lead design strategies, which can be followed depending on the type of information at hands.
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
computational chemistry services, in silico screening and drug design
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.
Bo Svensson, Computational Chemistry, SARomics Biostructures
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.

For related services please follow the respective link

protein X-ray crystallography services, gen-to-structure and off-the-shelf structures

Gene-to-structure services

protein NMR spectroscopy services, fragment screening and ligand binding

Protein NMR spectroscopy

antibody and antibody-antigen complex strucure charaterization, high order structure of biosimilars

Antibody structure

Structure-based design of biological drugs