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Second-Site NMR Screening and Linker Design

[ Vol. 3 , Issue. 1 ]


Wolfgang Jahnke, Andreas Florsheimer, Marcel J.J. Blommers, C. Gregory Paris, Jutta Heim, Carlo M. Nalin and Lawrence B. Perez   Pages 69 - 80 ( 12 )


One of the prime merits of NMR as a tool for lead finding in drug discovery research is its sensitivity and robustness to detect weak protein-ligand interactions. This sensitivity allows to build up ligands for a given target in a modular way, by a fragmentbased approach. In this approach, two ligands are seperately identified which bind to the target protein generally weakly, but at adjacent binding sites. In a next step, they are chemically linked to produce a high-affinity ligand. This review discusses methods to detect “second-site” ligands that bind to a protein in the presence of a “first-site” ligand, and methods to elucidate structural details on the spatial orientation of both ligands, so that chemical linkage is based on a large piece of experimental information. Published examples from second-site screening and linker design are summarized, and are complemented by previously unpublished in-house examples.


NMR Screening, protein


Novartis Pharma AG, Central Technologies, CH-4002 Basel, Switzerland

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