SAR-by-NMR

SAR-by-NMR represents a very intuitive way of rational, fragment-based drug design. Two or more independently optimized ligands of different binding sites are combined to give a high-affmity binder. The example presented here deals with the development of a selective inhibitor for the protein tyrosine phosphatase IB (PTPlB).6i 

PTPIB operates in the insulin-signalling pathway. When insulin binds to its receptor, there is a conformational change of intracellular region of the protein, which results in the 0-phosphorylation of three tyrosine residues as the first step in the cascade of the insulin signalling. PTPIB is reckoned to be responsible for the dephosphorylation of the insulin receptor. Dephosphorylation results in the down regulation of the insulin receptor and therefore selective inhibition of PTPIB may enhance insulin activity. 

Finally, this inhibitor was cross-checked against five other phosphatases to determine the selectivity. Among those analyzed, TCPTP is closely related to PTPIB on the basis of sequence homology. Therefore, a difference in the affinity of the evaluated compounds for these two enzymes would be a remarkable achievement. The relative selectivities are snmmarized in Table 4, indicating that compound 18 is indeed able to distinguish between PTPIB and TCPTP. 

This example underscores the efficiency of SAR-by-NMR and moreover illustrates the fragment-based approach. 

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Shuker S B, P J Hadjuk, R P Meadows and R P Fesik 1996. Discovering High-affinity Ligands fc Proteins SAR by NMR. Science 274 1531-1534. 

In its original form (version i), SAR-by-NMR involved the following steps ... 

Examples of the application of SAR-by-NMR include the design of stromelysin and human papillomavirus E2 protein inhibitors [7, 8]. 

Keywords NMR, drug discovery, fragment based drug discovery, SAR by NMR, SAR by ILOEs, hit to lead... 

Fig. 3 The SAR by NMR approach. Example of a small bidentate molecule designed using this approach. The example shown is for the design of a potent inhibitors of the matrix metalloproteinase MMP3. (a) Docked structures of the identified fragment leads are shown with cyan carbons, whereas the linked compound is shown with green carbon atoms. All structures were experimentally determined by NMR. (b) Chemical structures (and in vitro potencies) of the fragment leads and subsequent high-affinity linked compounds. Adapted from [7]...

Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins - SAR by NMR. Science 1996 274 1531-1534. 

Hajduk PJ, Sheppard G, Nettesheim DG, Olejniczak ET, Shuker SB, Meadows RP, Steinman DH, Carrera GM, Marcotte PA, Severin J, Walter K, Smith H, Gubbins E, Simmer R, Holzman TF, Morgan DW, Davidsen SK, Summers JB, Fesik SW. Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 1997 119 5818-5827. 

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... 

Fig. 18.1 Fragment combination strategies. Left In SAR by NMR [5], small molecular fragments that bind to the target are identified using protein-detected experiments. In the follow-up step, compounds bound in close proximity to one another are identified by chemical shift perturbation and intermolecular NOE experiments, and distance information is used to design and synthesize a linked compound. Center In fragment...

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