High sensitivity, high throughput
The wide applicability array-based surface plasmon resonance (SPR) has been demonstrated by screening an excess of 100 targets including many classes of enzymes and kinases, nuclear hormone receptors, protein-protein interaction targets and inherently disordered proteins. NovAliX SPR-array screens have seeded numerous hit to lead medicinal chemistry and fragment based drug discovery programs.
In common with the multitude of commercially available SPR instruments the proprietary NovAliX chemical microarray system detects the specific binding of analytes to an immobilized partner. Whereas in conventional instruments such as the Biacore™ soluble analytes flow over an immobilized protein, the NovAliX chemical microarray system operates in the opposite sense exposing immobilized small molecule / fragment to a solution of the protein.
This switch from a protein-based to small molecule ligand-based format is not trivial and has some profound implications. The technology and associated workflow is outcome of optimized photolithographic techniques, purpose built SPR imaging and fully integrated software packages for the processing and analysis of data.
What are the advantages of ligand-based screening?
High throughput. In a matter of a few days the novel and diverse NovAliB library of more than 116,000 immobilized fragments and lead-like compounds can be screened. Affinity data is delivered at a rate of >36,000 interactions per day per array reader using arrays of 9,216 ligands. The throughput of the array format is therefore better suited to primary screening than conventional commercial SPR instruments.
High sensitivity, ideal for the fragment screening, is the consequence of the large change in refractive index brought about by binding the larger protein partner rather than the small molecule.
High material efficiency both in the quantities of ligand and protein is a further advantage.
Unstable proteins may be analyzed quickly, before they deteriorate because all ligands on an array are exposed to the protein simultaneously. Array screening is also more fitting in cases of proteins that are deactivated by immobilization but are stable in solution.
NovAliX uses arrays to provide primary screening hits including confirmation of binding site specificity via competition assays.
T. Neumann et al. SPR Screening of Chemical Microarrays for Fragment-Based Discovery, in Label-Free Technologies for Drug Discovery, Ed. L Mayr, Wiley, 2011
A. HeimRiether, et.al. Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors , Bioorganic & Medicinal Chemistry Letters, 2009, 19(18), 5321-5324
T.Neumann et al. SPR Based Fragment Screening: Advantages and Applications, Current Topics in Medicinal Chemistry, 2007, 7, 1630-1642
T. Neumann, et al. Discovery of Thrombin Fragments from Chemical Microarray Screening, Letters in Drug Design & Discovery, 2005, 2, 563-566