Second-Site NMR Screening and Linker Design

Author(s): Wolfgang Jahnke, Andreas Florsheimer, Marcel J.J. Blommers, C. Gregory Paris, Jutta Heim, Carlo M. Nalin, Lawrence B. Perez.

Journal Name: Current Topics in Medicinal Chemistry

Volume 3 , Issue 1 , 2003

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Abstract:

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 Published examples from second-site screening and linker design are summarized, and are complemented by previously unpublished in-house examples.

Keywords: NMR Screening, protein

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Article Details

VOLUME: 3
ISSUE: 1
Year: 2003
Page: [69 - 80]
Pages: 12
DOI: 10.2174/1568026033392778

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