ZoBio is an established, market leading supplier of an array of biophysical techniques to support modern drug discovery efforts.
ZoBio has established and demonstrated the efficacy of its proprietary Target Immobilized NMR Screening (TINS) technology for the discovery of high quality, diverse fragment ligands for a wide array of challenging targets including membrane bound proteins, such as GPCRs.
More recently, we have added orthogonal validation technologies such as SPR and protein observed NMR. To further support Fragment- and Structure-based drug discovery, ZoBio has introduced highly innovative, NMR-based methods to rapidly elucidate the structure of target-small molecule complexes.
ZoBio has integrated these technologies into an efficient pipeline to support hit to clinical candidate programs on targets that no other CRO can address.
ZoBio offers its proprietary TINS technology for ligand screening studies on our own, highly validated fragment library or the customer’s. TINS uses a sample of the target and a reference protein that have been immobilized on sepharose based resin. Binding is detected by a reduction in the height of the NMR signals of a compound that specifically binds to the target. The screen is carried out by repeated cycles of fragment application, assaying for binding and fragment removal.
TINS is a powerful approach to hit discovery that has been validated on a wide range of targets including viral proteins, proteases, kinases, epigenetic targets, Protein-Protein Interaction targets, molecular chaperones and membrane proteins including GPCRs and ion channels. A typical TINS hit discovery project is completed in 1-2 months.
How does TINS work: http://www.zobio.com/index.php/technology
Hits from a TINS screen can be validated and characterized in a number of ways using TINS in competition mode, other NMR or SPR approaches. SPR is a powerful, industry accepted ligand discovery technology that is orthogonal to NMR. In particular, TINS and SPR are highly complementary since both require target immobilization while TINS provides extraordinary sensitivity to weak interactions and SPR is highly quantitative.
We have recently shown that a powerful work flow for a fragment discovery program is TINS screening followed by SPR fragment characterization (Kobayashi et al, J. Biomol. Screening, 2010, 15, p.978). ZoBio has a unique, highly integrated platform of TINS and SPR that allows us to further leverage our unparalleled expertise in protein immobilization for the benefit of our customers.
While crystallography is a powerful method to obtain high resolution structure information, it is not always successful. ZoBio has extensive experience in the elucidation of the 3D structure of target-ligand complexes using NMR. Starting with simple but efficient ligand based methods when protein observed methods are not applicable. If a protein can be isotope labelled and is of a moderate size (< 40 kDa) then the full range of NMR tools are available including binding site mapping and resonance assignment and structure elucidation via NOE.
For many proteins a structure may already be available. In such cases an alternative approach is available that is both efficient and accurate. Here, only the CH3 groups of I, L & V residues (depicted as balls in the graph) are isotope labelled. The red and blue methyl groups are sufficiently close (~8 Å) to 1H’s of the ligand to give rise to NOEs (schematically shown on the left). The intermolecular NOEs can be used to calculate the structure of the complex even when the target is 100 kDa or more.