SAR-by-NMR technique

A non-classical, but still rational and structure-based, screening approach was applied by researchers at Abbott Laboratories, utilizing the SAR-by-NMR technique [126, 127] to identify biophysically pTyr mimics for the Lck SH2... 

Recently, a potent inhibitor of Bcl-xL was discovered after applying the SAR by NMR technique to an initial hit from an NMR-based screen.1141 We applied NOE matching to one of the commercially available initial hits [4-fluorobiphenyl-4-carboxylic acid 7, Kd = 300 30 pM],... 

Figure 6 Illustration of the SAR-by-NMR technique. High-affinity binders are identified on the basis of two medium-affinity binders of different but adjacent binding sites...

Fragment-based screening Example NMR screening/SAR by NMR techniques... 

If the assignment is available or can be made in reasonable time (and preferably, but not necessarily, if the protein structure is approximately known), the location of the binding site may be easily derived. This method is currently implemented in the so-called SAR (Structure-Activity Relationship) by NMR technique [13]. 

For the 1H/I5N experiment, uniformly labeled substance is obtainable at a reasonable cost, but uniform 13C labeled proteins are more expensive. However, in some cases selective labeling of the methyl groups in valine, leucine, or isoleucine residues of a protein proves sufficient for screening purposes (59). The employment of HSQC experiments to detect binding is especially well exemplified in the technique termed SAR by NMR (33). 

Mechanistically, inhibition must not necessarily block the active site itself, but it can exert allosteric effects on the substrate-binding pocket, which thereby enhances or suppresses enzymatic activity. Additional considerations regarding enzymatic reactions are discussed in Reference 86. SAR by NMR has been successfully applied to various systems [i.e., for disrupting intracellular protein-protein binding (87) as well as cytokine-receptor interaction (88)]. High-affinity enzyme inhibitors have been developed by this technique [e.g., for the metalloproteinase Stromelysin (89) and the protein tyrosine phosphatase IB (90)]. 

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